CRYSTALLINE FORMS OF C21H22Cl2N4O2

ABSTRACT

The present invention provides crystalline forms of a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     Also provided are pharmaceutical compositions that include the provided crystalline forms and methods of using the provided crystalline forms and pharmaceutical compositions for the treatment of cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims the benefit to and is a continuation ofU.S. Non-provisional patent application Ser. No. 15/598,181, filed May17, 2017, which claims benefit to and is a continuation of U.S.Non-provisional patent application Ser. No. 15/011,377, filed Jan. 29,2016, now U.S. Pat. No. 9,676,746, which claims the benefit of U.S.Provisional Patent Application No. 62/110,449, filed Jan. 30, 2015, eachof which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to crystalline forms of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide, which is useful as aninhibitor of ERK protein kinase.

BACKGROUND OF THE INVENTION

Mitogen-activated protein kinase (MAPK) pathways mediate signals whichcontrol diverse cellular processes including growth, differentiation,migration, proliferation and apoptosis. One MAPK pathway, theextracellular signal-regulated kinase (ERK) signaling pathway, is oftenfound to be up-regulated in tumors. Pathway members, therefore,represent attractive blockade targets in the development of cancertherapies (Kohno and Pouyssegur, 2006). For example, U.S. Pat. No.7,354,939 B2 discloses, inter alia, compounds effective as inhibitors ofERK protein kinase. One of these compounds,4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide, is a compound according toformula (I):

Pharmaceutical compositions are often formulated with a crystallinesolid of the active pharmaceutical ingredient (API). The specificcrystalline form of the API can have significant effects on propertiessuch as stability and solubility/bioavailability. Instability andsolubility characteristics can limit the ability to formulate acomposition with an adequate shelf life or to effectively deliver adesired amount of a drug over a given time frame (Peterson et al.,2006).

There exists an unmet need for crystalline forms of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide which exhibit improvedproperties for formulation of pharmaceutical compositions. The presentapplication is directed to meeting this and other needs.

SUMMARY OF THE INVENTION

It has been discovered that crystalline forms of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide can be prepared which exhibitimproved properties, e.g. surprisingly improved stability and improvedsolubility characteristics.

Thus, the present invention provides crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide.

The present invention also provides crystalline free base4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide.

The present invention also provides a crystalline free base of acompound of formula:

having an X-ray powder diffraction (XRPD) pattern comprising acharacteristic peak at about 19.5° 2θ.

The present invention also provides a crystalline free base of acompound of formula:

having an XRPD pattern comprising characteristic peaks at about 9.1 and19.5° 2θ.

The present invention also provides a crystalline free base of acompound of formula:

having an XRPD pattern comprising characteristic peaks at about 9.1,15.4, 19.5 and 21.4° 2θ.

The present invention also provides a crystalline free base of acompound of formula:

having one or more XRPD 2θ-reflections (°) selected from the groupconsisting of about 9.1, 12.5, 15.2, 15.4, 19.2, 19.5, 20.3, 20.5, 21.4,21.7, 21.9, 23.1, 23.3, 23.6, and 24.3.

The present invention also provides a crystalline free base of acompound of formula:

having an XRPD pattern substantially as shown in FIG. 1.

The present invention also provides pharmaceutical compositionscomprising any of the crystalline compounds of the present invention.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of any of the crystalline compounds of the presentinvention.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of any of the pharmaceutical compositions of thepresent invention.

The present invention also provides crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an X-ray powder diffraction (XRPD) pattern comprising acharacteristic peak at about 6.7° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.7 and11.0° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.7,11.0, 17.6 and 19.9° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having one or more XRPD 2θ-reflections (°) selected from the groupconsisting of about 6.1, 6.7, 11.0, 12.1, 13.7, 15.2, 16.5, 17.6, 17.9,18.4, 18.7, 19.6, 19.9, and 20.4.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern substantially as shown in FIG. 4.

The present invention also provides crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl hydrate.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an X-ray powder diffraction (XRPD) pattern comprising acharacteristic peak at about 10.5° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.2 and10.5° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.2,10.5, 22.4 and 28.5° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having one or more XRPD 2θ-reflections (°) selected from the groupconsisting of about 5.8, 5.9, 6.2, 10.5, 11.8, 12.4, 15.9, 17.6, 17.8,20.0, 20.4, 21.1, 21.4, 21.9, 22.4, 23.1, 24.0, 24.2, 24.9, and 25.3.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern substantially as shown in FIG. 7.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an X-ray powder diffraction (XRPD) pattern comprising acharacteristic peak at about 10.7° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 10.7 and18.1° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.0,10.7, 12.7, and 18.1° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having one or more XRPD 2θ-reflections (°) selected from the groupconsisting of about 6.0, 6.3, 10.7, 12.0, 12.7, 15.6, 16.2, 16.3, 16.7,17.9, 18.1, and 21.4.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern substantially as shown in FIG. 10.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1 shows the XRPD of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide free base acquired intransmission mode.

FIG. 2 shows the FT-IR spectrum of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide free base.

FIG. 3 shows the DSC thermogram of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide free base.

FIG. 4 shows the XRPD of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C acquired in transmissionmode.

FIG. 5 shows the FT-IR spectrum of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C.

FIG. 6 shows the DSC thermogram of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C.

FIG. 7 shows the XRPD of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A acquired in transmissionmode.

FIG. 8 shows the FT-IR spectrum of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A.

FIG. 9 shows the DSC thermogram of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A.

FIG. 10 shows the XRPD of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form D acquired in reflectionmode.

FIG. 11 shows the FT-IR spectrum of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form D.

FIG. 12 shows the DSC thermogram of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form D.

FIG. 13 shows a comparison of the Raman spectra from 1000-1600 cm⁻¹ for4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Forms A and C.

FIG. 14 shows a comparison of the Raman spectra from 950-1030 cm⁻¹ for4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Forms A and C.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide.

The present invention also provides crystalline free base4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide.

The present invention also provides a crystalline free base of acompound of formula:

having an X-ray powder diffraction (XRPD) pattern comprising acharacteristic peak at about 19.5° 2θ.

The present invention also provides a crystalline free base of acompound of formula:

having an XRPD pattern comprising characteristic peaks at about 9.1 and19.5° 2θ.

The present invention also provides a crystalline free base of acompound of formula:

having an XRPD pattern comprising characteristic peaks at about 9.1,15.4, 19.5 and 21.4° 2θ.

The present invention also provides a crystalline free base of acompound of formula:

having one or more XRPD 2θ-reflections (°) selected from the groupconsisting of about 9.1, 12.5, 15.2, 15.4, 19.2, 19.5, 20.3, 20.5, 21.4,21.7, 21.9, 23.1, 23.3, 23.6, and 24.3.

The present invention also provides a crystalline free base of acompound of formula:

having an XRPD pattern substantially as shown in FIG. 1.

The present invention also provides crystalline free base4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having a Fouriertransform infrared spectroscopy (FT-IR) spectrum comprising one or morepeaks at about 1603, 1533, 1487, 1080, 857, and 681 cm⁻¹.

The present invention also provides crystalline free base4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having an FT-IRspectrum substantially as shown in FIG. 2.

The present invention also provides crystalline free base4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having (i) an XRPDpattern comprising one or more peaks at about 9.1, 15.4, 19.5 and 21.4°2θ; and (ii) a FT-IR spectrum comprising one or more peaks at about1603, 1533, 1487, 1080, 857, and 681 cm⁻¹.

The present invention also provides crystalline free base4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having a DSCthermogram with an endotherm having an onset temperature ofapproximately 184° C.

The present invention also provides crystalline free base4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having a DSCthermogram substantially as shown in FIG. 3.

The present invention also provides a pharmaceutical compositioncomprising a crystalline compound of the present invention.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of a crystalline compound of the present invention.

In some embodiments, the subject is a mammal.

In some embodiments, the mammal is selected from the group consisting ofhumans, primates, farm animals, and domestic animals.

In some embodiments, the mammal is a human.

In some embodiments, the method further comprises administering to thesubject at least one additional anti-cancer agent.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of a pharmaceutical composition of the presentinvention.

In some embodiments, the subject is a mammal.

In some embodiments, the mammal is selected from the group consisting ofhumans, primates, farm animals, and domestic animals.

In some embodiments, the mammal is a human.

In some embodiments, the method further comprises administering to thesubject at least one additional anti-cancer agent.

The present invention also provides crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an X-ray powder diffraction (XRPD) pattern comprising acharacteristic peak at about 6.7° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.7 and11.0° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.7,11.0, 17.6 and 19.9° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having one or more XRPD 2θ-reflections (°) selected from the groupconsisting of about 6.1, 6.7, 11.0, 12.1, 13.7, 15.2, 16.5, 17.6, 17.9,18.4, 18.7, 19.6, 19.9, and 20.4.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern substantially as shown in FIG. 4.

The present invention also provides form C crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having a Fouriertransform infrared spectroscopy (FT-IR) spectrum comprising one or morepeaks at about 1610, 1523, 1219, 1141, 1076, and 845 cm⁻¹.

The present invention also provides form C crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having an FT-IRspectrum substantially as shown in FIG. 5.

The present invention also provides form C crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having (i) an XRPDpattern comprising one or more peaks at about 6.7, 11.0, 17.6, and 19.9°2θ; and (ii) a FT-IR spectrum comprising one or more peaks at about1610, 1523, 1219, 1141, 1076, and 845 cm⁻¹.

The present invention also provides form C crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having a DSCthermogram with an endotherm having an onset temperature ofapproximately 239° C.

The present invention also provides form C crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having a DSCthermogram substantially as shown in FIG. 6.

The present invention also provides a pharmaceutical compositioncomprising a crystalline compound of the present invention.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of a crystalline compound of the present invention.

In some embodiments, the subject is a mammal.

In some embodiments, the mammal is selected from the group consisting ofhumans, primates, farm animals, and domestic animals.

In some embodiments, the mammal is a human.

In some embodiments, the method further comprises administering to thesubject at least one additional anti-cancer agent.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of a pharmaceutical composition of the presentinvention.

In some embodiments, the subject is a mammal.

In some embodiments, the mammal is selected from the group consisting ofhumans, primates, farm animals, and domestic animals.

In some embodiments, the mammal is a human.

In some embodiments, the method further comprises administering to thesubject at least one additional anti-cancer agent.

The present invention also provides crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl hydrate.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an X-ray powder diffraction (XRPD) pattern comprising acharacteristic peak at about 10.5° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.2 and10.5° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.2,10.5, 22.4 and 28.5° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having one or more XRPD 2θ-reflections (°) selected from the groupconsisting of about 5.8, 5.9, 6.2, 10.5, 11.8, 12.4, 15.9, 17.6, 17.8,20.0, 20.4, 21.1, 21.4, 21.9, 22.4, 23.1, 24.0, 24.2, 24.9, and 25.3.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern substantially as shown in FIG. 7.

The present invention also provides form A crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl hydrate having a Fouriertransform infrared spectroscopy (FT-IR) spectrum comprising one or morepeaks at about 1573, 1237, 1163, 946, and 790 cm⁻¹.

The present invention also provides form A crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl hydrate having an FT-IRspectrum substantially as shown in FIG. 8.

The present invention also provides form A crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl hydrate having (i) an XRPDpattern comprising one or more peaks at about 6.2, 10.5, 22.4, and 28.5°2θ; and (ii) a FT-IR spectrum comprising one or more peaks at about1573, 1237, 1163, 946, and 790 cm⁻¹.

The present invention also provides form A crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl hydrate having a DSCthermogram substantially as shown in FIG. 9.

The present invention also provides a pharmaceutical compositioncomprising a crystalline compound of the present invention.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of a crystalline compound of the present invention.

In some embodiments, the subject is a mammal.

In some embodiments, the mammal is selected from the group consisting ofhumans, primates, farm animals, and domestic animals.

In some embodiments, the mammal is a human.

In some embodiments, the method further comprises administering to thesubject at least one additional anti-cancer agent.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of a pharmaceutical composition of the presentinvention.

In some embodiments, the subject is a mammal.

In some embodiments, the mammal is selected from the group consisting ofhumans, primates, farm animals, and domestic animals.

In some embodiments, the mammal is a human.

In some embodiments, the method further comprises administering to thesubject at least one additional anti-cancer agent.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an X-ray powder diffraction (XRPD) pattern comprising acharacteristic peak at about 10.7° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 10.7 and18.1° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.0,10.7, 12.7, and 18.1° 2θ.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having one or more XRPD 2θ-reflections (°) selected from the groupconsisting of about 6.0, 6.3, 10.7, 12.0, 12.7, 15.6, 16.2, 16.3, 16.7,17.9, 18.1, and 21.4.

The present invention also provides a crystalline hydrochloride salt ofa compound of formula:

having an XRPD pattern substantially as shown in FIG. 10.

The present invention also provides form D crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl having a Fourier transforminfrared spectroscopy (FT-IR) spectrum comprising one or more peaks atabout 1537, 1471, 1239, 1163, 1067, and 946 cm⁻¹.

The present invention also provides form D crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl having an FT-IR spectrumsubstantially as shown in FIG. 11.

The present invention also provides form D crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl having (i) an XRPD patterncomprising one or more peaks at about 6.0, 12.7, and 18.1° 2θ; and (ii)a FT-IR spectrum comprising one or more peaks at about 1537, 1471, 1239,1163, 1067, and 946 cm⁻¹.

The present invention also provides form D crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl having a DSC thermogramsubstantially as shown in FIG. 12.

The present invention also provides a pharmaceutical compositioncomprising a crystalline compound of the present invention.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of a crystalline compound of the present invention.

In some embodiments, the subject is a mammal.

In some embodiments, the mammal is selected from the group consisting ofhumans, primates, farm animals, and domestic animals.

In some embodiments, the mammal is a human.

In some embodiments, the method further comprises administering to thesubject at least one additional anti-cancer agent.

The present invention also provides a method of treating a cancer in asubject in need thereof comprising administering to the subject aneffective amount of a pharmaceutical composition of the presentinvention.

In some embodiments, the subject is a mammal.

In some embodiments, the mammal is selected from the group consisting ofhumans, primates, farm animals, and domestic animals.

In some embodiments, the mammal is a human.

In some embodiments, the method further comprises administering to thesubject at least one additional anti-cancer agent.

The term “solid form” is often used to refer to a class or type ofsolid-state material. One kind of solid form is a “polymorph” whichrefers to two or more compounds having the same chemical formula butdiffering in solid-state structure. Salts may be polymorphic. Whenpolymorphs are elements, they are termed allotropes. Carbon possessesthe well-known allotropes of graphite, diamond, andbuckminsterfullerene. Polymorphs of molecular compounds, such as activepharmaceutical ingredients (“APIs”), are often prepared and studied inorder to identify compounds meeting scientific or commercial needsincluding, but not limited to, improved solubility, dissolution rate,hygroscopicity, and stability.

Other solid forms include solvates and hydrates of compounds includingsalts. A solvate is a compound wherein a solvent molecule is present inthe crystal structure together with another compound, such as an API.When the solvent is water, the solvent is termed a hydrate. Solvates andhydrates may be stoichiometric or non-stoichiometric. A monohydrate isthe term used when there is one water molecule, stoichiometrically, withrespect to, for example, an API, in the unit cell.

In order to identify the presence of a particular solid form, one ofordinary skill typically uses a suitable analytical technique to collectdata on the form for analysis. For example, chemical identity of solidforms can often be determined with solution-state techniques such as¹³C-NMR or ¹H-NMR spectroscopy and such techniques may also be valuablein determining the stoichiometry and presence of “guests” such as wateror solvent in a hydrate or solvate, respectively. These spectroscopictechniques may also be used to distinguish, for example, solid formswithout water or solvent in the unit cell (often referred to as“anhydrates”), from hydrates or solvates.

Solution-state analytical techniques do not provide information aboutthe solid state as a substance and thus, for example, solid-statetechniques may be used to distinguish among solid forms such asanhydrates. Examples of solid-state techniques which may be used toanalyze and characterize solid forms, including anhydrates and hydrates,include single crystal X-ray diffraction, X-ray powder diffraction(“XRPD”), solid-state ¹³C-NMR, Infrared (“IR”) spectroscopy, includingFourier Transform Infrared (FT-IR) spectroscopy, Raman spectroscopy, andthermal techniques such as Differential Scanning calorimetry (DSC),melting point, and hot stage microscopy.

Polymorphs are a subset of crystalline forms that share the samechemical structure but differ in how the molecules are packed in asolid. When attempting to distinguish polymorphs based on analyticaldata, one looks for data which characterize the form. For example, whenthere are two polymorphs of a compound (e.g., Form I and Form II), onecan use X-ray powder diffraction peaks to characterize the forms whenone finds a peak in a Form I pattern at angles where no such peak ispresent in the Form II pattern. In such a case, that single peak forForm I distinguishes it from Form II and may further act to characterizeForm I. When more forms are present, then the same analysis is also donefor the other polymorphs. Thus, to characterize Form I against the otherpolymorphs, one would look for peaks in Form I at angles where suchpeaks are not present in the X-ray powder diffraction patterns of theother polymorphs. The collection of peaks, or indeed a single peak,which distinguishes Form I from the other known polymorphs is acollection of peaks which may be used to characterize Form I. If, forexample, two peaks characterize a polymorph then those two peaks can beused to identify the presence of that polymorph and hence characterizethe polymorph. Those of ordinary skill in the art will recognize thatthere are often multiple ways, including multiple ways using the sameanalytical technique, to characterize polymorphic polymorphs. Forexample, one may find that three X-ray powder diffraction peakscharacterize a polymorph. Additional peaks could also be used, but arenot necessary, to characterize the polymorph up to and including anentire diffraction pattern. Although all the peaks within an entirediffractogram may be used to characterize a crystalline form, one mayinstead, and typically does as disclosed herein, use a subset of thatdata to characterize such a crystalline form depending on thecircumstances.

For example, as used herein, “characteristic peaks” are a subset ofobserved peaks and are used to differentiate one crystalline polymorphfrom another crystalline polymorph. Characteristic peaks are determinedby evaluating which observed peaks, if any, are present in onecrystalline polymorph of a compound against all other known crystallinepolymorphs of that compound to within ±0.2° 2θ.

When analyzing data to distinguish an anhydrate from a hydrate, forexample, one can rely on the fact that the two solid forms havedifferent chemical structures—one having water in the unit cell and theother not. Thus, this feature alone may be used to distinguish the formsof the compound and it may not be necessary to identify peaks in theanhydrate, for example, which are not present in the hydrate or viceversa.

X-ray powder diffraction patterns are some of the most commonly usedsolid-state analytical techniques used to characterize solid forms. AnX-ray powder diffraction pattern is an x-y graph with the diffractionangle, 2θ (°), on the x-axis and intensity on the y-axis. The peakswithin this plot may be used to characterize a crystalline solid form.The data is often represented by the position of the peaks on the x-axisrather than the intensity of peaks on the y-axis because peak intensitycan be particularly sensitive to sample orientation (see PharmaceuticalAnalysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is nottypically used by those skilled in the art to characterize solid forms.

As with any data measurement, there is variability in X-ray powderdiffraction data. In addition to the variability in peak intensity,there is also variability in the position of peaks on the x-axis. Thisvariability can, however, typically be accounted for when reporting thepositions of peaks for purposes of characterization. Such variability inthe position of peaks along the x-axis derives from several sources. Onecomes from sample preparation. Samples of the same crystalline material,prepared under different conditions may yield slightly differentdiffractograms. Factors such as particle size, moisture content, solventcontent, and orientation may all affect how a sample diffracts X-rays.Another source of variability comes from instrument parameters.Different X-ray instruments operate using different parameters and thesemay lead to slightly different diffraction patterns from the samecrystalline solid form. Likewise, different software packages processX-ray data differently and this also leads to variability. These andother sources of variability are known to those of ordinary skill in thepharmaceutical arts.

Due to such sources of variability, it is common to recite X-raydiffraction peaks using the word “about” prior to the peak value indegrees (2θ) (sometimes expressed herein as “2θ-reflections (°)”), whichpresents the data to within 0.1 or 0.20 (2θ) of the stated peak valuedepending on the circumstances. The X-ray powder diffraction datacorresponding to the solid forms of the present invention were collectedon instruments which were routinely calibrated and operated by skilledscientists. In the present invention, XRPD values are preferablyobtained using Cu Kα X-ray radiation according to the method describedin Example 1. Accordingly, the variability associated with these datawould be expected to be closer to ±0.1° 2θ than to ±0.2° 2θ and indeedlikely less than 0.1 with the instruments used herein. However, to takeinto account that instruments used elsewhere by those of ordinary skillin the art may not be so maintained, for example, all X-ray powderdiffraction peaks cited herein have been reported with a variability onthe order of ±0.2° 2θ and are intended to be reported with such avariability whenever disclosed herein and are reported in thespecification to one significant figure after the decimal even thoughanalytical output may suggest higher precision on its face.

Single-crystal X-ray diffraction provides three-dimensional structuralinformation about the positions of atoms and bonds in a crystal. It isnot always possible or feasible, however, to obtain such a structurefrom a crystal, due to, for example, insufficient crystal size ordifficulty in preparing crystals of sufficient quality forsingle-crystal X-ray diffraction.

X-ray powder diffraction data may also be used, in some circumstances,to determine the crystallographic unit cell of the crystallinestructure. The method by which this is done is called “indexing.”Indexing is the process of determining the size and shape of thecrystallographic unit cell consistent with the peak positions in asuitable X-ray powder diffraction pattern. Indexing provides solutionsfor the three unit cell lengths (a, b, c), three unit cell angles (α, β,γ), and three Miller index labels (h, k, l) for each peak. The lengthsare typically reported in Angstrom units and the angles in degree units.The Miller index labels are unitless integers. Successful indexingindicates that the sample is composed of one crystalline phase and istherefore not a mixture of crystalline phases.

IR spectroscopy, particularly FT-IR, is another technique that may beused to characterize solid forms together with or separately from X-raypowder diffraction. In an IR spectrum, absorbed light is plotted on thex-axis of a graph in the units of “wavenumber” (cm⁻¹), with intensity onthe y-axis. Variation in the position of IR peaks also exists and may bedue to sample conditions as well as data collection and processing. Thetypical variability in IR spectra reported herein is on the order ofplus or minus 2.0 cm⁻¹. Thus, the use of the word “about” whenreferencing IR peaks is meant to include this variability and all IRpeaks disclosed herein are intended to be reported with suchvariability.

Thermal methods are another typical technique to characterize solidforms. Different polymorphs of the same compound often melt at differenttemperatures. Thus, the melting point of a polymorph, as measured bymethods such as capillary melting point, DSC, and hot stage microscopy,alone or in combination with techniques such as X-ray powderdiffraction, IR spectroscopy, including FT-IR, or both, may be used tocharacterize polymorphs or other solid forms.

As with any analytical technique, melting point determinations are alsosubject to variability. Common sources of variability, in addition toinstrumental variability, are due to colligative properties such as thepresence of other solid forms or other impurities within a sample whosemelting point is being measured.

As used herein, the terms “treat,” “treating,” “treatment” andgrammatical variations thereof mean subjecting an individual subject toa protocol, regimen, process or remedy, in which it is desired to obtaina physiologic response or outcome in that subject, e.g., a patient. Inparticular, the methods and compositions of the present invention may beused to slow the development of disease symptoms or delay the onset ofthe disease or condition, or halt the progression of diseasedevelopment. However, because every treated subject may not respond to aparticular treatment protocol, regimen, process or remedy, treating doesnot require that the desired physiologic response or outcome be achievedin each and every subject or subject population, e.g., patientpopulation. Accordingly, a given subject or subject population, e.g.,patient population may fail to respond or respond inadequately totreatment.

As used herein, the terms “ameliorate”, “ameliorating” and grammaticalvariations thereof mean to decrease the severity of the symptoms of adisease in a subject.

As used herein, a “subject” is a mammal, preferably, a human. Inaddition to humans, categories of mammals within the scope of thepresent invention include, for example, farm animals, domestic animals,laboratory animals, etc. Some examples of farm animals include cows,pigs, horses, goats, etc. Some examples of domestic animals includedogs, cats, etc. Some examples of laboratory animals include primates,rats, mice, rabbits, guinea pigs, etc.

Cancers include both solid and hemotologic cancers. Non-limitingexamples of solid cancers include adrenocortical carcinoma, anal cancer,bladder cancer, bone cancer (such as osteosarcoma), brain cancer, breastcancer, carcinoid cancer, carcinoma, cervical cancer, colon cancer,endometrial cancer, esophageal cancer, extrahepatic bile duct cancer,Ewing family of cancers, extracranial germ cell cancer, eye cancer,gallbladder cancer, gastric cancer, germ cell tumor, gestationaltrophoblastic tumor, head and neck cancer, hypopharyngeal cancer, isletcell carcinoma, kidney cancer, large intestine cancer, laryngeal cancer,leukemia, lip and oral cavity cancer, liver cancer, lung cancer,lymphoma, malignant mesothelioma, Merkel cell carcinoma, mycosisfungoides, myelodysplastic syndrome, myeloproliferative disorders,nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer,osteosarcoma, ovarian epithelial cancer, ovarian germ cell cancer,pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroidcancer, penile cancer, pituitary cancer, plasma cell neoplasm, prostatecancer, rhabdomyosarcoma, rectal cancer, renal cell cancer, transitionalcell cancer of the renal pelvis and ureter, salivary gland cancer,Sézary syndrome, skin cancers (such as cutaneous t-cell lymphoma,Kaposi's sarcoma, mast cell tumor, and melanoma), small intestinecancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymoma,thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvarcancer, and Wilms' tumor.

Examples of hematologic cancers include, but are not limited to,leukemias, such as adult/childhood acute lymphoblastic leukemia,adult/childhood acute myeloid leukemia, chronic lymphocytic leukemia,chronic myelogenous leukemia, and hairy cell leukemia, lymphomas, suchas AIDS-related lymphoma, cutaneous T-cell lymphoma, adult/childhoodHodgkin lymphoma, mycosis fungoides, adult/childhood non-Hodgkinlymphoma, primary central nervous system lymphoma, Sézary syndrome,cutaneous T-cell lymphoma, and Waldenstrom macroglobulinemia, as well asother proliferative disorders such as chronic myeloproliferativedisorders, Langerhans cell histiocytosis, multiple myeloma/plasma cellneoplasm, myelodysplastic syndromes, andmyelodysplastic/myeloproliferative neoplasms. A preferred set of cancersthat may be treated according to the present invention includeneuroblastoma, leukemia, lymphoma, liver cancer, lung cancer, skincancer, testicular cancer, and thyroid cancer. Preferably, the cancer ismelanoma.

The methods of the present invention may optionally further includeadministering to the subject at least one additional therapeutic agenteffective for treating or ameliorating the effects of the cancer. Theadditional therapeutic agent may be selected from the group consistingof an antibody or fragment thereof, a chemotherapeutic agent, animmunotherapeutic agent, a radionuclide, a photoactive therapeuticagent, a radiosensitizing agent, and combinations thereof.

The crystalline, free base, and salt forms of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide (hereinafter “solid forms ofthe present invention”) and the anti-cancer agent(s) used in theco-treatment therapy may be administered to the subject, eithersimultaneously or at different times, as deemed most appropriate. If thesolid forms of the present invention and the other anti-cancer agent(s)are administered at different times, for example, by serialadministration, then the solid forms of the present invention may beadministered to the subject before the other anti-cancer agent.Alternatively, the other anti-cancer agent(s) may be administered to thesubject before the4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide.

As used herein, an “antibody” encompasses naturally occurringimmunoglobulins as well as non-naturally occurring immunoglobulins,including, for example, single chain antibodies, chimeric antibodies(e.g., humanized murine antibodies), and heteroconjugate antibodies(e.g., bispecific antibodies). Fragments of antibodies include thosethat bind antigen, (e.g., Fab′, F(ab′)2, Fab, Fv, and rIgG). See also,e.g., Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co.,Rockford, Ill.); Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., NewYork (1998). The term antibody also includes bivalent or bispecificmolecules, diabodies, triabodies, and tetrabodies. The term “antibody”further includes both polyclonal and monoclonal antibodies.

Examples of therapeutic antibodies that may be used in the presentinvention include rituximab (Rituxan), Cetuximab (Erbitux), bevacizumab(Avastin), and Ibritumomab (Zevalin).

As used herein, “chemotherapeutic agent” means any therapeutic agentthat is compatible with the solid forms of the present inventiontreatment of the present invention and that uses cytotoxic and/orcytostatic agents against cancer cells or cells that are associated withor support cancer cells. In a preferred embodiment, the chemotherapeuticagent is an agent selected from the group consisting of ananti-metabolite, a microtubule inhibitor, a DNA damaging agent, anantibiotic, an anti-angiogenesis agent, a vascular disrupting agent, amolecularly targeted agent, and combinations thereof.

As used herein, an “anti-metabolite” is a substance that reduces orinhibits a cell's use of a chemical that is part of normal metabolism.Non-limiting examples of anti-metabolite agents or analogs thereofaccording to the present invention include antifolates, purineinhibitors, pyrimidine inhibitors, and combinations thereof.

As used herein, an “antifolate” is a substance that alters, reduces, orinhibits the use of folic acid (vitamin B9) by cells. Non-limitingexamples of antifolates include methotrexate (DuraMed Pharmaceuticals,Inc.), pemetrexed (Eli Lilly), pralatrexate (Spectrum Pharmaceuticals),aminopterin (Sigma Aldrich), pharmaceutically acceptable salts thereof,and combinations thereof.

As used herein, a “purine” is a compound that contains a fusedsix-membered and a five-membered nitrogen-containing ring. Non-limitingexamples of purines that are important for cellular metabolism includeadenine, guanine, hypoxanthine, and xanthine. A “purine inhibitor” is asubstance that alters, reduces or suppresses the production of a purineor the use of a purine by a cell. Non-limiting examples of purineinhibitors include methotrexate (DuraMed Pharmaceuticals, Inc.),pemetrexed (Eli Lilly), hydroxyurea (Bristol-Myers Squibb),2-mercaptopurine (Sigma-Aldrich), 6-mercaptopurine (Sigma-Aldrich),fludarabine (Ben Venue Laboratories), clofarabine (Genzyme Corp.),nelarabine (GlaxoSmithKline), pralatrexate (Spectrum Pharmaceuticals),6-thioguanine (Gate Pharmaceuticals), forodesine (BioCrystPharmaceuticals), pentostatin (Bedford Laboratories), sapacitabine(Cyclacel Pharmaceuticals, Inc.), aminopterin (Sigma Aldrich),azathioprine (GlaxoSmithKline), pharmaceutically acceptable saltsthereof, and combinations thereof.

As used herein, a “pyrimidine” is a compound that contains asix-membered nitrogen-containing ring. Non-limiting examples ofpyrimidines that are important for cellular metabolism include uracil,thymine, cytosine, and orotic acid. A “pyrimidine inhibitor” is asubstance that alters, reduces, or suppresses the production of apyrimidine or the use of a pyrimidine by the a cell. Non-limitingexamples of pyrimidine inhibitors include 5-fluorouracil (TocrisBioscience), tegafur (LGM Pharma), capecitabine (Xeloda) (Roche),cladribine (LGM Pharma), gemcitabine (Eli Lilly), cytarabine (BedfordLaboratories), decitabine (Eisai Inc.), floxuridine (BedfordLaboratories), 5-azacytidine (Pharmion Pharmaceuticals), doxifluridine(Cayman Chemicals), thiarabine (Access Pharmaceuticals), troxacitabine(SGX Pharmaceuticals), raltitrexed (AstraZeneca), carmofur (Santa CruzBiotechnology, Inc.), 6-azauracil (MP Biomedicals, LLC),pharmaceutically acceptable salts thereof, and combinations thereof.

In a preferred aspect of the present invention, the anti-metaboliteagent is selected from the group consisting of 5-fluorouracil (TocrisBioscience), tegafur (LGM Pharma), capecitabine (Xeloda) (Roche),cladribine (LGM Pharma), methotrexate (DuraMed Pharmaceuticals, Inc.),pemetrexed (Eli Lilly), hydroxyurea (Bristol-Myers Squibb),2-mercaptopurine (Sigma-Aldrich), 6-mercaptopurine (Sigma-Aldrich),fludarabine (Ben Venue Laboratories), gemcitabine (Eli Lilly),clofarabine (Genzyme Corp.), cytarabine (Bedford Laboratories),decitabine (Eisai Inc.), floxuridine (Bedford Laboratories), nelarabine(GlaxoSmithKline), pralatrexate (Spectrum Pharmaceuticals),6-thioguanine (Gate Pharmaceuticals), 5-azacytidine (PharmionPharmaceuticals), doxifluridine (Cayman Chemicals), forodesine (BioCrystPharmaceuticals), pentostatin (Bedford Laboratories), sapacitabine(Cyclacel Pharmaceuticals, Inc.), thiarabine (Access Pharmaceuticals),troxacitabine (SGX Pharmaceuticals), raltitrexed (AstraZeneca),aminopterin (Sigma Aldrich), carmofur (Santa Cruz Biotechnology, Inc.),azathioprine (GlaxoSmithKline), 6-azauracil (MP Biomedicals, LLC),pharmaceutically acceptable salts thereof, and combinations thereof.

As used herein, a “microtubule inhibitor” is a substance that disruptsthe functioning of a microtubule, such as the polymerization or thedepolymerization of individual microtubule units. In one aspect of thepresent invention, the microtubule inhibitor may be selected from thegroup consisting of a microtubule-destabilizing agent, amicrotubule-stabilizing agent, and combinations thereof. A microtubuleinhibitor of the present invention may also be selected from the groupconsisting of a taxane, a vinca alkaloid, an epothilone, andcombinations thereof. Non-limiting examples of microtubule inhibitorsaccording to the present invention include BT-062 (Biotest), HMN-214 (D.Western Therapeutics), eribulin mesylate (Eisai), vindesine (Eli Lilly),EC-1069 (Endocyte), EC-1456 (Endocyte), EC-531 (Endocyte), vintafolide(Endocyte), 2-methoxyestradiol (EntreMed), GTx-230 (GTx), trastuzumabemtansine (Hoffmann-La Roche), crolibulin (Immune Pharmaceuticals),D1302A-maytansinoid conjugates (ImmunoGen), IMGN-529 (ImmunoGen),lorvotuzumab mertansine (ImmunoGen), SAR-3419 (ImmunoGen), SAR-566658(ImmunoGen), IMP-03138 (Impact Therapeutics), topotecan/vincristinecombinations (LipoCure), BPH-8 (Molecular Discovery Systems),fosbretabulin tromethamine (OXiGENE), estramustine phosphate sodium(Pfizer), vincristine (Pierre Fabre), vinflunine (Pierre Fabre),vinorelbine (Pierre Fabre), RX-21101 (Rexahn), cabazitaxel (Sanofi),STA-9584 (Synta Pharmaceuticals), vinblastine, epothilone A, patupilone(Novartis), ixabepilone (Bristol-Myers Squibb), Epothilone D (KosanBiosciences), paclitaxel (Bristol-Myers Squibb), docetaxel(Sanofi-Aventis), HAI abraxane, DJ-927 (Daiichi Sankyo), discodermolide(CAS No: 127943-53-7), eleutherobin (CAS No.: 174545-76-7),pharmaceutically acceptable salts thereof, and combinations thereof.

DNA damaging agents of the present invention include, but are notlimited to, alkylating agents, platinum-based agents, intercalatingagents, and inhibitors of DNA replication.

As used herein, an “alkylating agent” is a substance that adds one ormore alkyl groups (CnHm, where n and m are integers) to a nucleic acid.In the present invention, an alkylating agent is selected from the groupconsisting of nitrogen mustards, nitrosoureas, alkyl sulfonates,triazines, ethylenimines, and combinations thereof. Non-limitingexamples of nitrogen mustards include mechlorethamine (Lundbeck),chlorambucil (GlaxoSmithKline), cyclophosphamide (Mead Johnson Co.),bendamustine (Astellas), ifosfamide (Baxter International), melphalan(Ligand), melphalan flufenamide (Oncopeptides), and pharmaceuticallyacceptable salts thereof. Non-limiting examples of nitrosoureas includestreptozocin (Teva), carmustine (Eisai), lomustine (Sanofi), andpharmaceutically acceptable salts thereof. Non-limiting examples ofalkyl sulfonates include busulfan (Jazz Pharmaceuticals) andpharmaceutically acceptable salts thereof. Non-limiting examples oftriazines include dacarbazine (Bayer), temozolomide (Cancer ResearchTechnology), and pharmaceutically acceptable salts thereof. Non-limitingexamples of ethylenimines include thiotepa (Bedford Laboratories),altretamine (MGI Pharma), and pharmaceutically acceptable salts thereof.Other alkylating agents include ProLindac (Access), Ac-225 BC-8(Actinium Pharmaceuticals), ALF-2111 (Alfact Innovation), trofosfamide(Baxter International), MDX-1203 (Bristol-Myers Squibb),thioureidobutyronitrile (CellCeutix), mitobronitol (Chinoin), mitolactol(Chinoin), nimustine (Daiichi Sankyo), glufosfamide (EleisonPharmaceuticals), HuMax-TAC and PBD ADC combinations (Genmab), BP-C1(Meabco), treosulfan (Medac), nifurtimox (Metronomx), improsulfantosilate (Mitsubishi tanabe Pharma), ranimustine (Mitsubishi tanabePharma), ND-01 (NanoCarrier), HH-1 (Nordic Nanovector), 22P1G cells andifosfamide combinations (Nuvilex), estramustine phosphate (Pfizer),prednimustine (Pfizer), lurbinectedin (PharmaMar), trabectedin(PharmaMar), altreatamine (Sanofi), SGN-CD33A (Seattle Genetics),fotemustine (Servier), nedaplatin (Shionogi), heptaplatin (Sk Holdings),apaziquone (Spectrum Pharmaceuticals), SG-2000 (Spirogen), TLK-58747(Telik), Iaromustine (Vion Pharmaceuticals), procarbazine (AlkemLaboratories Ltd.), and pharmaceutically acceptable salts thereof.

As used herein, a “platinum-based agent” is an anti-cancer substancethat contains the metal platinum and analogs of such substances. Theplatinum may be in any oxidation state. Platinum-based agents of thepresent invention include, but are not limited to,1,2-diaminocyclohexane (DACH) derivatives, phenanthroimidazole Pt(II)complexes, platiunum IV compounds, bi- and tri-nuclear platinumcompounds, demethylcantharidin-integrated platinum complexes,platinum-conjugated compounds, cisplatin nanoparticles and polymermicelles, sterically hindered platinum complexes, oxaliplatin(Debiopharm), satraplatin (Johnson Matthey), BBR3464 (NovuspharmaS.p.A.), ZD0473 (Astra Zeneca), cisplatin (Nippon Kayaku), JM-11(Johnson Matthey), PAD (cis-dichlorobiscyclopentylamine platinum (II)),MBA ((trans-1,2-diaminocyclohexane) bisbromoacetato platinum (II)), PHM((1,2-Cyclohexanediamine) malonato platinum (II)), SHP((1,2-Cyclohexanediamine) sulphato platinum (II)), neo-PHM((trans-R,R-1,2-Cyclohexanediamine) malonato platinum (II)), neo-SHP((trans-R,R-1,2-Cyclohexanediamine)sulphato platinum (II)), JM-82(Johnson Matthey), PYP ((1,2-Cyclohexanediamine) bispyruvato platinum(II)), PHIC ((1,2-Cyclohexanediamine) isocitrato platinum (II)), TRK-710((trans-R,R-1,2-cyclohexanediamine)[3-Acetyl-5-methyl-2,4(3H,5H)-furandionato] platinum (II)), BOP((1,2-Cyclooctanediamine) bisbromoacetato platinum (II)), JM-40 (JohnsonMatthey), enloplatin (UnionPharma), zeniplatin (LGM Pharma), CI-973(Parke-Davis), lobaplatin (Zentaris AG/Hainan Tianwang InternationalPharmaceutical), cycloplatam (LGM Pharma), WA2114R(miboplatin/lobaplatin) (Chembest Research Laboratories, Ltd.),heptaplatin (SK12053R) (SK Chemicals), TNO-6 (spiroplatin) (HaihangIndustry Co., Ltd.), ormaplatin (tetraplatin) (LGM Pharma), JM-9(iproplatin) (Johnson Matthey), BBR3610 (Novuspharma S.p.A.), BBR3005(Novuspharma S.p.A.), BBR3571 (Novuspharma S.p.A.), BBR3537 (NovuspharmaS.p.A.), aroplatin (L-NDDP) (BOC Sciences), Pt-ACRAMTU ({[Pt(en)CI(ACRAMTU-S)](NO3)2 (en=ethane-1,2-diamine,ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea)}),cisplatin-loaded liposomes (LiPlasomes), SPI-077 (Alza), lipoplatin(Regulon), lipoxal (Regulon), carboplatin (Johnson Matthey), nedaplatin(Shionogi Seiyaku), miriplatin hydrate (Dainippon Sumitomo Pharma),ormaplatin (LGM Pharma), enloplatin (Lederle Laboratories), C1973(Parke-Davis), PEGylated cisplatin, PEGylated carboplatin, PEGylatedoxaliplatin, transplatin (trans-diamminedichloroplatinum(II);mixedZ:trans-[PtCl2{Z-HN═C(OMe)Me}(NH3)]), CD-37 (estradiol-platinum(II)hybrid molecule), picoplatin (Poniard Pharmaceuticals),

AH44 (Komeda et al., 2006; Harris et al., 2005; Qu et al., 2004),triplatinNC (Harris et al., 2005; Qu et al., 2004), ProLindac (Access),pharmaceutically acceptable salts thereof, and combinations thereof.

As used herein, an “intercalating agent” includes, but is not limitedto, doxorubicin (Adriamycin), daunorubicin, idarubicin, mitoxantrone,pharmaceutically acceptable salts thereof, prodrugs, and combinationsthereof.

Non-limiting examples of inhibitors of DNA replication include, but arenot limited to topoisomerase inhibitors. As used herein, a“topoisomerase inhibitor” is a substance that decreases the expressionor the activity of a topoisomerase. The topoisomerase inhibitorsaccording to the present invention may inhibit topoisomerase I,topoisomerase II, or both topoisomerase I and topoisomerase II.Non-limiting examples of topoisomerase I inhibitors according to thepresent invention include irinotecan (Alchemia), APH-0804 (Aphios),camptothecin (Aphios), cositecan (BioNumerik), topotecan(GlaxoSmithKline), belotecan hydrochloride (Chon Kun Dang), firtecanpegol (Enzon), HN-30181A (Hanmi), hRS7-SN-38 (Immunomedics),labetuzumab-SN-38 (Immunomedics), etirinotecan pegol (NektarTherapeutics), NK-012 (Nippon Kayaku), SER-203 (Serina Therapeutics),simmitecan hydrochloride prodrug (Shanghai HaiHe Pharmaceuticals),gimatecan (Sigma-Tau), namitecan (Sigma-Tau), SN-38 (Supratek Pharma),TLC-388 hydrochloride (Taiwan Liposome Company), lamellarin D(PharmaMar), pharmaceutically acceptable salts thereof, and combinationsthereof. Non-limiting examples of inhibitors of topoisomerase type IIaccording to the present invention include Adva-27a (Advanomics),zoptarelin doxorubicin (Aeterna Zentaris), valrubicin (AnthraPharmaceuticals), razoxane (AstraZeneca), doxorubicin (AvenaTherapeutics), amsacrine (Bristol-Myers Squibb), etoposide phosphate(Bristol-Myers Squibb), etoposide (Novartis), dexrazoxane (CancerResearch Technology), cytarabine/daunorubicin combination (CelatorPharmaceuticals), CAP7.1 (CellAct Pharma), aldoxorubicin (CytRx),amrubicin hydrochloride (Dainippon Sumitomo Pharma), vosaroxin(Dainippon Sumitomo Pharma), daunorubicin (Gilead Sciences),milatuzumab/doxorubicin combination (Immunomedics), aclarubicin (KyowaHakko Kirin), mitoxantrone (Meda), pirarubicin (Meiji), epirubicin(Pfizer), teniposide (Novartis), F-14512 (Pierre Fabre), elliptiniumacetate (Sanofi), zorubicin (Sanofi), dexrazoxane (TopoTarget),sobuzoxane (Zenyaku Kogyo), idarubicin (Pfizer), HU-331 (CaymanChemical), aurintricarboxylic acid (Sigma Aldrich), pharmaceuticallyacceptable salts thereof, and combinations thereof.

Chemotherapeutic antibiotics according to the present invention include,but are not limited to, actinomycin, anthracyclines, valrubicin,epirubicin, bleomycin, plicamycin, mitomycin, pharmaceuticallyacceptable salts thereof, prodrugs, and combinations thereof.

As used herein, the term “anti-angiogenesis agent” means any compoundthat prevents or delays nascent blood vessel formation from existingvessels. In the present invention, examples of anti-angiogenesis agentsinclude, but are not limited to, pegaptanib, ranibizumab, bevacizumab(avastin), carboxyamidotriazole, TNP-470, CM101, IFN-α, IL-12, plateletfactor 4, suramin, SU5416, thrombospondin, VEGFR antagonists,angiostatic steroids and heparin, cartilage-derived angiogenesisinhibitory factor, matrix metalloproteinase inhibitors, angiostatin,endostatin, 2-methoxyestradiol, tecogalan, prolactin, αvβ3 inhibitors,linomide, VEGF-Trap, aminosterols, cortisone, tyrosine kinaseinhibitors, anti-angiogenic siRNA, inhibitors of the complement system,vascular disrupting agents, and combinations thereof. Preferably, theanti-angiogenesis agent is bevacizumab.

VEGFR antagonists of the present invention include, but are not limitedto, pazopanib, regorafenib, lenvatinib, sorafenib, sunitinib, axitinib,vandetanib, cabozantinib, vatalanib, semaxanib, ZD6474, SU6668,AG-013736, AZD2171, AEE788, MF1/MC-18F1, DC101/IMC-1C11, ramucirumab,and motesanib. VEGFR antagonists may also include, VEGF inhibitors suchas bevacizumab, aflibercept, 2C3, r84, VEGF-Trap, and ranibizumab.

Angiostatic steroids of the present invention include any steroid thatinhibits, attenuates, prevents angiogenesis or neovascularization, orcauses regression of pathological vascularization. Angiostatic steroidsof the present invention include those disclosed in European PatentApplication Serial No. EP1236471 A2, as well as those 20-substitutedsteroids disclosed in U.S. Pat. No. 4,599,331, those 21-hydroxy steroidsdisclosed in U.S. Pat. No. 4,771,042, those C11-functionalized steroidsdisclosed in International Application Serial No. WO 1987/02672,6α-fluoro17α,21-dihydroxy-16α-methylpregna-4,9(11)-diene-3,20-dione21-acetate,6α-fluoro-17α,21-dihydroxy-16β-methylpregna-4,9(11)-diene-3,20-dione,6α-fluoro-17α,21-dihydroxy-16β-methylpregna-4,9(11)-diene-3,20-dione21-phosphonooxy and pharmaceutically acceptable salts thereof,hydrocortisone, tetrahydrocortisol, 17α-hydroxy-progesterone,11α-epihydrocortisone, cortexolone, corticosterone,desoxycorticosterone, dexamethasone, cortisone 21-acetate,hydrocortisone 21-phosphate, 17α-hydroxy-6α-methylpregn-4-ene-3,20-dione17-acetate,6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(11)-diene-3,20-dione,and Δ9(11)-etianic esters, all disclosed in International ApplicationSerial No. WO 1990/015816 A1.

Cartilage-derived angiogenesis inhibitor factors include, but are notlimited to, peptide troponin and chondromodulin I.

Matrix metalloproteinase inhibitors of the present invention include,but are not limited to, succinyl hydroxamates such as marimastat andSC903, sulphonamide hydroxamates such as CGS27023A, phosphinamidehydroxamates, carboxylate inhibitors such as BAY12-9566, thiolinhibitors such as Compound B, aminomethyl benzimidazole analogues,peptides such as regasepin, and tetracyclines such as minocycline.

αvβ3 inhibitors include, but are not limited to, IS20I, P11 peptide, EMD85189, and 66203, RGD peptide, RGD mimetics such as S 36578-2,echistatin, antibodies or antibody fragments against αvβ3 integrin suchas Vitaxin, which targets the extracellular domain of the dimer,cilengitide, and peptidomimetics such as S247.

Anti-angiogenic siRNAs include, but are not limited to, siRNAs targetingmRNAs that are upregulated during angiogenesis, optionally PEGylatedsiRNAs targeting VEGF or VEGFR mRNAs, and siRNAs targeting UPR (unfoldedprotein response)-IRE1α, XBP-1, and ATF6 mRNAs. Additionally, it hasbeen shown that siRNAs that are, at minimum, 21 nucleotides in length,regardless of targeting sequence, suppress neovascularization (Kleinman,et al., 2008) and may be included in the anti-angiogenic siRNAs of thepresent invention.

Inhibitors of the complement system include, but are not limited to,modified native complement components such as soluble complementreceptor type 1, soluble complement receptor type 1 lacking longhomologous repeat-A, soluble Complement Receptor Type 1-Sialyl Lewisx,complement receptor type 2, soluble decay accelerating factor, solublemembrane cofactor protein, soluble CD59, decay accelerating factor-CD59hybrid, membrane cofactor protein-decay accelerating factor hybrid, C1inhibitor, and C1q receptor, complement-inhibitory antibodies such asanti-C5 monoclonal antibody and anti-C5 single chain Fv, syntheticinhibitors of complement activation such as antagonistic peptides andanalogs targeting C5a receptor, and naturally occurring compounds thatblock complement activation such as heparin and relatedglycosaminoglycan compounds. Additional inhibitors of the complementsystem are disclosed by Makrides (Makrides, 1998).

As used herein, the term “vascular disrupting agent” means any compoundthat targets existing vasculature, e.g. tumor vasculature, damages ordestroys said vasculature, and/or causes central tumor necrosis. In thepresent invention, examples of vascular disrupting agents include, butare not limited to, ABT-751 (Abbott), AVE8062 (Aventis), BCN105(Bionomics), BMXAA (Antisoma), CA-4-P (OxiGene), CA-1-P (OxiGene),CYT997 (Cytopia), MPC-6827 (Myriad Pharmaceuticals), MN-029(MediciNova), NPI-2358 (Nereus), Oxi4503 (Oxigene), TZT-1027 (DaichiPharmaceuticals), ZD6126 (AstraZeneca and Angiogene), pharmaceuticallyacceptable salts thereof, and combinations thereof.

As used herein, a “molecularly targeted agent” is a substance thatinterferes with the function of a single molecule or group of molecules,preferably those that are involved in tumor growth and progression, whenadministered to a subject. Non-limiting examples of molecularly targetedagents of the present invention include signal transduction inhibitors,modulators of gene expression and other cellular functions, immunesystem modulators, antibody-drug conjugates (ADCs), and combinationsthereof.

As used herein, a “signal transduction inhibitor” is a substance thatdisrupts communication between cells, such as when an extracellularsignaling molecule activates a cell surface receptor. Non-limitingexamples of signal transduction inhibitors of the present inventioninclude anaplastic lymphoma kinase (ALK) inhibitors, B-Raf inhibitors,epidermal growth factor inhibitors (EGFRi), ERK inhibitors, Janus kinaseinhibitors, MEK inhibitors, mammalian target of rapamycin (mTor)inhibitors, phosphoinositide 3-kinase inhibitors (PI3Ki), and Rasinhibitors.

As used herein, an “anaplastic lymphoma kinase (ALK) inhibitor” is asubstance that (i) directly interacts with ALK, e.g., by binding to ALKand (ii) decreases the expression or the activity of ALK. Non-limitingexamples of anaplastic lymphoma kinase (ALK) inhibitors of the presentinvention include crizotinib (Pfizer, New York, N.Y.), CH5424802 (ChugaiPharmaceutical Co., Tokyo, Japan), GSK1838705 (GlaxoSmithKline, UnitedKingdom), Chugai 13d (Chugai Pharmaceutical Co., Tokyo, Japan), CEP28122(Teva Pharmaceutical Industries, Ltd., Israel), AP26113 (AriadPharmaceuticals, Cambridge, Mass.), Cephalon 30 (Teva PharmaceuticalIndustries, Ltd., Israel), X-396 (Xcovery, Inc., West Palm Beach, Fla.),Amgen 36 (Amgen Pharmaceuticals, Thousand Oaks, Calif.), ASP3026(Astellas Pharma US, Inc., Northbrook, Ill.), and Amgen 49 (AmgenPharmaceuticals, Thousand Oaks, Calif.), pharmaceutically acceptablesalts thereof, and combinations thereof.

As used herein, a “B-Raf inhibitor” of the present invention is asubstance that (i) directly interacts with B-Raf, e.g., by binding toB-Raf and (ii) decreases the expression or the activity of B-Raf. B-Rafinhibitors may be classified into two types by their respective bindingmodes. As used herein, “Type 1” B-Raf inhibitors are those inhibitorsthat target the ATP binding sites of the kinase in its activeconformation. “Type 2” B-Raf inhibitors are those inhibitors thatpreferentially bind to an inactive conformation of the kinase.Non-limiting examples of Type 1 B-Raf inhibitors of the presentinvention include:

dabrafenib (GlaxoSmithKline), GDC-0879 (Genentech), L-779450 B-Raf(Merck), PLX3202 (Plexxikon), PLX4720 (Plexxikon), SB-590885(GlaxoSmithKline), SB-699393 (GlaxoSmithKline), vemurafenib (Plexxikon),pharmaceutically acceptable salts thereof, and combinations thereof.Preferably, the type 1 RAF inhibitor is dabrafenib or a pharmaceuticallyacceptable salt thereof.

Non-limiting examples of Type 2 B-Raf inhibitors of the presentinvention include:

Sorafenib (Onyx Pharmaceuticals), ZM-336372 (AstraZeneca),pharmaceutically acceptable salts thereof, and combinations thereof

Other B-Raf inhibitors include, without limitation, AAL881 (Novartis);AB-024 (Ambit Biosciences), ARQ-736 (ArQule), ARQ-761 (ArQule), AZ628(Axon Medchem BV), BeiGene-283 (BeiGene), BIIB-024 (MLN 2480) (Sunesis &Takeda), b raf inhibitor (Sareum), BRAF kinase inhibitor (SelexagenTherapeutics), BRAF siRNA 313 (tacaccagcaagctagatgca) and 253(cctatcgttagagtcttcctg) (Liu et al., 2007), CTT239065 (Institute ofCancer Research), DP-4978 (Deciphera Pharmaceuticals), HM-95573 (Hanmi),GW 5074 (Sigma Aldrich), ISIS 5132 (Novartis), LErafAON (NeoPharm,Inc.), LBT613 (Novartis), LGX 818 (Novartis), pazopanib(GlaxoSmithKline), PLX5568 (Plexxikon), RAF-265 (Novartis), RAF-365(Novartis), regorafenib (Bayer Healthcare Pharmaceuticals, Inc.), RO5126766 (Hoffmann-La Roche), TAK 632 (Takeda), TL-241 (Teligene), XL-281(Exelixis), pharmaceutically acceptable salts thereof, and combinationsthereof.

As used herein, an “EGFR inhibitor” is a substance that (i) directlyinteracts with EGFR, e.g. by binding to EGFR and (ii) decreases theexpression or the activity of EGFR. Non-limiting examples of EGFRinhibitors according to the present invention include (+)-Aeroplysinin-1(CAS #28656-91-9), 3-(4-Isopropylbenzylidenyl)-indolin-2-one, ABT-806(Life Science Pharmaceuticals), AC-480 (Bristol-Myers Squibb), afatinib(Boehringer Ingelheim), AG 1478 (CAS #153436-53-4), AG 494 (CAS#133550-35-3), AG 555 (CAS #133550-34-2), AG 556 (CAS #133550-41-1), AG825 (CAS #149092-50-2), AG-490 (CAS #134036-52-5), antroquinonol (GoldenBiotechnology), AP-26113 (Ariad), ARRY334543 (CAS #845272-21-1), AST1306 (CAS #897383-62-9), AVL-301 (Celgene), AZD8931 (CAS #848942-61-0),BIBU 1361 (CAS #793726-84-8), BIBX 1382 (CAS #196612-93-8), BMS-690514(Bristol-Myers Squibb), BPIQ-I (CAS #174709-30-9), Canertinib (Pfizer),cetuximab (Actavis), cipatinib (Jiangsu Hengrui Medicine), CL-387,785(Santa Cruz Biotech), compound 56 (CAS #171745-13-4), CTX-023 (CytomXTherapeutics), CUDC-101 (Curis), dacomitinib (Pfizer), DAPH (CAS#145915-58-8), daphnetin (Santa Cruz Biotech), dovitinib lactate(Novartis), EGFR Inhibitor (CAS #879127-07-8), epitinib (Hutchison ChinaMediTech), erbstatin Analog (CAS #63177-57-1), erlotinib (Astellas),gefitinib (AstraZeneca), GT-MAB 5.2-GEX (Glycotope), GW 583340 (CAS#388082-81-3), GW2974 (CAS #202272-68-2), HDS 029 (CAS #881001-19-0),Hypericin (Santa Cruz Biotech), icotinib hydrochloride (Betapharma),JNJ-26483327 (Johnson & Johnson), JNJ-28871063 (Johnson & Johnson),KD-020 (Kadmon Pharmaceuticals), lapatinib ditosylate (GlaxoSmithKline),Lavendustin A (Sigma), Lavendustin C (Sigma), LY-3016859 (Eli Lilly),MEHD-7945A (Hoffmann-La Roche), MM-151 (Merrimack), MT-062 (MedisynTechnologies), necitumumab (Eli Lilly), neratinib (Pfizer), nimotuzumab(Center of Molecular Immunology), NT-004 (NewGen Therapeutics),pantiumumab (Amgen), PD 153035 (CAS #153436-54-5), PD 161570 (CAS#192705-80-9), PD 168393, PD 174265 (CAS #216163-53-0), pirotinib(Sihuan Pharmaceutical), poziotinib (Hanmi), PP 3 (CAS #5334-30-5),PR-610 (Proacta), pyrotinib (Jiangsu Hengrui Medicine), RG-13022 (CAS#136831-48-6), rindopepimut (Celldex Therapeutics), RPI-1 (CAS#269730-03-2), S-222611 (Shionogi), TAK 285 (CAS #871026-44-7), TAS-2913(Taiho), theliatinib (Hutchison China MediTech), Tyrphostin 47(RG-50864, AG-213) (CAS #118409-60-2), Tyrphostin 51 (CAS #122520-90-5),Tyrphostin AG 1478 (CAS #175178-82-2), Tyrphostin AG 183 (CAS#126433-07-6), Tyrphostin AG 528 (CAS #133550-49-9), Tyrphostin AG 99(CAS #118409-59-9), Tyrphostin B42 (Santa Cruz Biotech), Tyrphostin B44(Santa Cruz Biotech), Tyrphostin RG 14620 (CAS #136831-49-7), vandetanib(AstraZeneca), varlitinib (Array BioPharma), vatalanib (Novartis), WZ3146 (CAS #1214265-56-1), WZ 4002 (CAS #1213269-23-8), WZ8040 (CAS#1214265-57-2), XL-647 (Exelixis), Z-650 (HEC Pharm), ZM 323881 (CAS#324077-30-7), pharmaceutically acceptable salts thereof, andcombinations thereof. Preferably, the EGFR inhibitor is selected fromthe group consisting of panitumumab, erlotinib, pharmaceuticallyacceptable salts thereof, and combinations thereof.

As noted above, the solid forms of the present invention are ERKinhibitors. As used herein, an “ERK inhibitor” is a substance that (i)directly interacts with ERK, including ERK1 and ERK2, e.g., by bindingto ERK and (ii) decreases the expression or the activity of an ERKprotein kinase. Therefore, inhibitors that act upstream of ERK, such asMEK inhibitors and RAF inhibitors, are not ERK inhibitors according tothe present invention. The solid forms of the present invention may beadministered as a combination therapy together with other ERKinhibitors, which include, for example, AEZS-131 (Aeterna Zentaris),AEZS-136 (Aeterna Zentaris), SCH-722984 (Merck & Co.), SCH-772984 (Merck& Co.), SCH-900353 (MK-8353) (Merck & Co.), pharmaceutically acceptablesalts thereof, and combinations thereof.

As used herein, a “Janus kinase inhibitor” is a substance that (i)directly interacts with a Janus kinase, e.g., by binding to a Januskinase and (ii) decreases the expression or the activity of a Januskinase. Janus kinases of the present invention include Tyk2, Jak1, Jak2,and Jak3. Non-limiting examples of Janus kinase inhibitors of thepresent invention include ruxolitinib (Incyte Corporation, Wilmington,Del.), baricitinib (Incyte Corporation, Wilmington, Del.), tofacitinib(Pfizer, New York, N.Y.), VX-509 (Vertex Pharmaceuticals, Inc., Boston,Mass.), GLPG0634 (Galapagos NV, Belgium), CEP-33779 (TevaPharmaceuticals, Israel), pharmaceutically acceptable salts thereof, andcombinations thereof

As used herein, a “MEK inhibitor” is a substance that (i) directlyinteracts with MEK, e.g., by binding to MEK and (ii) decreases theexpression or the activity of MEK. Therefore, inhibitors that actupstream of MEK, such as RAS inhibitors and RAF inhibitors, are not MEKinhibitors according to the present invention. MEK inhibitors may beclassified into two types depending on whether the inhibitor competeswith ATP. As used herein, a “Type 1” MEK inhibitor is an inhibitor thatcompetes with ATP for binding to MEK. A “Type 2” MEK inhibitor is aninhibitor that does not compete with ATP for binding to MEK.Non-limiting examples of type 1 MEK inhibitors according to the presentinvention include bentamapimod (Merck KGaA), L783277 (Merck), RO092210(Roche), pharmaceutically acceptable salts thereof, and combinationsthereof. Preferably, the type 1 MEK inhibitor is RO092210 (Roche) or apharmaceutically acceptable salt thereof. Non-limiting examples of type2 MEK inhibitors according to the present invention include anthraxtoxin, lethal factor portion of anthrax toxin, ARRY-142886(6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide) (Array BioPharma), ARRY-438162 (ArrayBioPharma), AS-1940477 (Astellas), MEK162 (Array BioPharma), PD 098059(2-(2′-amino-3′-methoxyphenyl)-oxanaphthalen-4-one), PD 184352(C01-1040), PD-0325901 (Pfizer), pimasertib (Santhera Pharmaceuticals),refametinib (AstraZeneca), selumetinib (AZD6244) (AstraZeneca), TAK-733(Takeda), trametinib (Japan Tobacco), U0126(1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) (Sigma),RDEA119 (Ardea Biosciences/Bayer), pharmaceutically acceptable saltsthereof, and combinations thereof. Preferably, the type 2 MEK inhibitoris trametinib or a pharmaceutically acceptable salt thereof. Other MEKinhibitors include, without limitation, antroquinonol (GoldenBiotechnology), AS-1940477 (Astellas), AS-703988 (Merck KGaA), BI-847325(Boehringer Ingelheim), E-6201 (Eisai), GDC-0623 (Hoffmann-La Roche),GDC-0973, RG422, RO4987655, RO5126766, SL327, WX-554 (Wilex), YopJpolypeptide, pharmaceutically acceptable salts thereof, and combinationsthereof.

As used herein, an “mTOR inhibitor” is a substance that (i) directlyinteracts with mTOR, e.g. by binding to mTOR and (ii) decreases theexpression or the activity of mTOR. Non-limiting examples of mTORinhibitors according to the present invention include zotarolimus(AbbVie), umirolimus (Biosensors), temsirolimus (Pfizer), sirolimus(Pfizer), sirolimus NanoCrystal (Elan Pharmaceutical Technologies),sirolimus TransDerm (TransDerm), sirolimus-PNP (Samyang), everolimus(Novartis), biolimus A9 (Biosensors), ridaforolimus (Ariad), rapamycin,TCD-10023 (Terumo), DE-109 (MacuSight), MS-R001 (MacuSight), MS-R002(MacuSight), MS-R003 (MacuSight), Perceiva (MacuSight), XL-765(Exelixis), quinacrine (Cleveland BioLabs), PKI-587 (Pfizer),PF-04691502 (Pfizer), GDC-0980 (Genentech and Piramed), dactolisib(Novartis), CC-223 (Celgene), PWT-33597 (Pathway Therapeutics), P-7170(Piramal Life Sciences), LY-3023414 (Eli Lilly), INK-128 (Takeda),GDC-0084 (Genentech), DS-7423 (Daiichi Sankyo), DS-3078 (DaiichiSankyo), CC-115 (Celgene), CBLC-137 (Cleveland BioLabs), AZD-2014(AstraZeneca), X-480 (Xcovery), X-414 (Xcovery), EC-0371 (Endocyte),VS-5584 (Verastem), PQR-401 (Piqur), PQR-316 (Piqur), PQR-311 (Piqur),PQR-309 (Piqur), PF-06465603 (Pfizer), NV-128 (Novogen), nPT-MTOR(Biotica Technology), BC-210 (Biotica Technology), WAY-600 (BioticaTechnology), WYE-354 (Biotica Technology), WYE-687 (Biotica Technology),LOR-220 (Lorus Therapeutics), HMPL-518 (Hutchison China MediTech),GNE-317 (Genentech), EC-0565 (Endocyte), CC-214 (Celgene), and ABTL-0812(Ability Pharmaceuticals).

As used herein, a “PI3K inhibitor” is a substance that decreases theexpression or the activity of phosphatidylinositol-3 kinases (PI3Ks) ordownstream proteins, such as Akt. PI3Ks, when activated, phosphorylatethe inositol ring 3′-OH group in inositol phospholipids to generate thesecond messenger phosphatidylinositol-3,4,5-trisphosphate(PI-3,4,5-P(3)). Akt interacts with a phospholipid, causing it totranslocate to the inner membrane, where it is phosphorylated andactivated. Activated Akt modulates the function of numerous substratesinvolved in the regulation of cell survival, cell cycle progression andcellular growth.

Non-limiting examples of PI3K inhibitors according to the presentinvention include A-674563 (CAS #552325-73-2), AGL 2263, AMG-319 (Amgen,Thousand Oaks, Calif.), AS-041164(5-benzo[1,3]dioxol-5-ylmethylene-thiazolidine-2,4-dione), AS-604850(5-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethylene)-thiazolidine-2,4-dione),AS-605240 (5-quinoxilin-6-methylene-1,3-thiazolidine-2,4-dione), AT7867(CAS #857531-00-1), benzimidazole series, Genentech (Roche HoldingsInc., South San Francisco, Calif.), BML-257 (CAS #32387-96-5), CAL-120(Gilead Sciences, Foster City, Calif.), CAL-129 (Gilead Sciences),CAL-130 (Gilead Sciences), CAL-253 (Gilead Sciences), CAL-263 (GileadSciences), CAS #612847-09-3, CAS #681281-88-9, CAS #75747-14-7, CAS#925681-41-0, CAS #98510-80-6, CCT128930 (CAS #885499-61-6), CH5132799(CAS #1007207-67-1), CHR-4432 (Chroma Therapeutics, Ltd., Abingdon, UK),FPA 124 (CAS #902779-59-3), GS-1101 (CAL-101) (Gilead Sciences), GSK690693 (CAS #937174-76-0), H-89 (CAS #127243-85-0), Honokiol, IC87114(Gilead Science), IPI-145 (Intellikine Inc.), KAR-4139 (KarusTherapeutics, Chilworth, UK), KAR-4141 (Karus Therapeutics), KIN-1(Karus Therapeutics), KT 5720 (CAS #108068-98-0), Miltefosine, MK-2206dihydrochloride (CAS #1032350-13-2), ML-9 (CAS #105637-50-1),Naltrindole Hydrochloride, OXY-111A (NormOxys Inc., Brighton, Mass.),perifosine, PHT-427 (CAS #1191951-57-1), PI3 kinase delta inhibitor,Merck KGaA (Merck & Co., Whitehouse Station, N.J.), PI3 kinase deltainhibitors, Genentech (Roche Holdings Inc.), PI3 kinase deltainhibitors, Incozen (Incozen Therapeutics, Pvt. Ltd., Hydrabad, India),PI3 kinase delta inhibitors-2, Incozen (Incozen Therapeutics), PI3kinase inhibitor, Roche-4 (Roche Holdings Inc.), PI3 kinase inhibitors,Roche (Roche Holdings Inc.), PI3 kinase inhibitors, Roche-5 (RocheHoldings Inc.), PI3-alpha/delta inhibitors, Pathway Therapeutics(Pathway Therapeutics Ltd., South San Francisco, Calif.), PI3-deltainhibitors, Cellzome (Cellzome AG, Heidelberg, Germany), PI3-deltainhibitors, Intellikine (Intellikine Inc., La Jolla, Calif.), PI3-deltainhibitors, Pathway Therapeutics-1 (Pathway Therapeutics Ltd.),PI3-delta inhibitors, Pathway Therapeutics-2 (Pathway TherapeuticsLtd.), PI3-delta/gamma inhibitors, Cellzome (Cellzome AG),PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gammainhibitors, Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors,Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors, PathwayTherapeutics (Pathway Therapeutics Ltd.), PI3-delta/gamma inhibitors,Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-gamma inhibitorEvotec (Evotec), PI3-gamma inhibitor, Cellzome (Cellzome AG), PI3-gammainhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3Kdelta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), PI3Kdelta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), pictilisib(GDC-0941) (Roche Holdings Inc.), PIK-90 (CAS #677338-12-4), SC-103980(Pfizer, New York, N.Y.), SF-1126 (Semafore Pharmaceuticals,Indianapolis, Ind.), SH-5, SH-6, Tetrahydro Curcumin, TG100-115(Targegen Inc., San Diego, Calif.), Triciribine, X-339 (Xcovery, WestPalm Beach, Fla.), XL-499 (Evotech, Hamburg, Germany), pharmaceuticallyacceptable salts thereof, and combinations thereof. Preferably, theinhibitor of the PI3K/Akt pathway is pictilisib (GDC-0941) or apharmaceutically acceptable salt thereof.

As used herein, a “RAS inhibitor” is a substance that (i) directlyinteracts with RAS, e.g., by binding to RAS and (ii) decreases theexpression or the activity of RAS. Non-limiting examples of RASinhibitors according to the present invention include farnesyltransferase inhibitors (such as, e.g., tipifarnib and lonafarnib),farnesyl group-containing small molecules (such as, e.g., salirasib andTLN-4601), DCAI, as described by Maurer (Maurer, et al., 2012), Kobe0065and Kobe2602, as described by Shima (Shima, et al., 2013), and HBS 3(Patgiri, et al., 2011), and AIK-4 (Allinky), pharmaceuticallyacceptable salts thereof, and combinations thereof.

As used herein, “gene expression” is a process by which the informationfrom DNA is used in the formation of a polypeptide. A “modulator of geneexpression and other cellular functions” is a substance that affectsgene expression and other works of a cell. Non-limiting examples of suchmodulators include hormones, histone deacetylase inhibitors (HDACi), andcyclin-dependent kinase inhibitors (CDKi), and poly ADP ribosepolymerase (PARP) inhibitors.

In the present invention, a “hormone” is a substance released by cellsin one part of a body that affects cells in another part of the body.Non-limiting examples of hormones according to the present inventioninclude prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin,antimullerian hormone, adiponectin, adrenocorticotropic hormone,angiotensinogen, angiotensin, vasopressin, atriopeptin, brainnatriuretic peptide, calcitonin, cholecystokinin,corticotropin-releasing hormone, encephalin, endothelin, erythropoietin,follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon,gonadotropin-releasing hormone, growth hormone-releasing hormone, humanchorionic gonadotropin, human placental lactogen, growth hormone,inhibin, insulin, somatomedin, leptin, liptropin, luteinizing hormone,melanocyte stimulating hormone, motilin, orexin, oxytocin, pancreaticpolypeptide, parathyroid hormone, prolactin, prolactin releasinghormone, relaxin, renin, secretin, somatostain, thrombopoietin,thyroid-stimulating hormone, testosterone, dehydroepiandrosterone,androstenedione, dihydrotestosterone, aldosterone, estradiol, estrone,estriol, cortisol, progesterone, calcitriol, and calcidiol.

Some compounds interfere with the activity of certain hormones or stopthe production of certain hormones. Non-limiting examples ofhormone-interfering compounds according to the present invention includetamoxifen (Nolvadex®), anastrozole (Arimidex®), letrozole (Femara®), andfulvestrant (Faslodex®). Such compounds are also within the meaning ofhormone in the present invention.

As used herein, an “HDAC inhibitor” is a substance that (i) directlyinteracts with HDAC, e.g., by binding to HDAC and (ii) decreases theexpression or the activity of HDAC. Non-limiting examples of HDACinhibitors according to the present invention include 4SC-201 (4SC AG),4SC-202 (Takeda), abexinostat (Celera), AN-1 (Titan Pharmaceuticals,Inc.), Apicidine (Merck & Co., Inc.), AR-42 (Arno Therapeutics),ARQ-700RP (ArQule), Avugane (TopoTarget AS),azelaic-1-hydroxamate-9-anilide (AAHA), belinostat (TopoTarget),butyrate (Enzo Life Sciences, Inc.), CG-1255 (Errant Gene Therapeutics,LLC), CG-1521 (Errant Gene Therapeutics, LLC), CG-200745(CrystalGenomics, Inc.), chidamide (Shenzhen Chipscreen Biosciences),CHR-3996 (Chroma Therapeutics), CRA-024781 (Pharmacyclics), CS-3158(Shenzhen Chipscreen Biosciences), CU-903 (Curis), DAC-60 (Genextra),entinostat (Bayer), hyaluronic acid butyric acid ester (HA-But), IKH-02(IkerChem), IKH-35 (IkerChem), ITF-2357 (Italfarmaco), ITF-A(Italfarmaco), JNJ-16241199 (Johnson & Johnson), KA-001 (KarusTherapeutics), KAR-3000 (Karus Therapeutics), KD-5150 (Kalypsys),KD-5170 (Kalypsys), KLYP-278 (Kalypsys), KLYP-298 (Kalypsys), KLYP-319(Kalypsys), KLYP-722 (Kalypsys), m-carboxycinnamic acid bis-hydroxamide(CBHA), MG-2856 (MethylGene), MG-3290 (MethylGene), MG-4230(MethylGene), MG-4915 (MethylGene), MG-5026 (MethylGene), MGCD-0103(MethylGene Inc.), mocetinostat (MethylGene), MS-27-275 (Schering AG),NBM-HD-1 (NatureWise), NVP-LAQ824 (Novartis), OCID-4681-S-01 (OrchidPharmaceuticals), oxamflatin ((2E)-5-[3-[(phenylsufonyl) aminolphenyl]-pent-2-en-4-ynohydroxamic acid), panobinostat (Novartis),PCI-34051 (Pharmacyclics), phenylbutyrate (Enzo Life Sciences, Inc.),pivaloyloxymethyl butyrate (AN-9, Titan Pharmaceuticals, Inc.), pivanex(Titan Pharmaceuticals, Inc.), pracinostat (SBIO), PX-117794 (TopoTargetAS), PXD-118490 (LEO-80140) (TopoTarget AS), pyroxamide (suberoyl-3-aminopyridineamide hydroxamic acid), resminostat (Takeda), RG-2833(RepliGen), ricolinostat (Acetylon), romidepsin (Astellas), SB-1304(S*BIO), SB-1354 (S*BIO), SB-623 (Merrion Research I Limited), SB-624(Merrion Research I Limited), SB-639 (Merrion Research I Limited),SB-939 (S*BIO), Scriptaid(N-Hydroxy-1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-hexan amide), SK-7041(In2Gen/SK Chemical Co.), SK-7068 (In2Gen/SK Chemical Co.),suberoylanilide hydroxamic acid (SAHA), sulfonamide hydroxamic acid,tributyrin (Sigma Aldrich), trichostatin A (TSA) (Sigma Aldrich),valporic acid (VPA) (Sigma Aldrich), vorinostat (Zolinza), WF-27082B(Fujisawa Pharmaceutical Company, Ltd.), pharmaceutically acceptablesalts thereof, and combinations thereof. Preferably, the HDAC inhibitoris romidepsin, pharmaceutically acceptable salts thereof, andcombinations thereof.

As used herein, “CDK” is a family of protein kinases that regulate thecell cycle. Known CDKs include cdk1, cdk2, ckd3, ckd4, cdk5, cdk6, cdk7,cdk8, cdk9, cdk10, and cdk11. A “CDK inhibitor” is a substance that (i)directly interacts with CDK, e.g. by binding to CDK and (ii) decreasesthe expression or the activity of CDK. Non-limiting examples of CDKinhibitors according to the present invention include 2-Hydroxybohemine,3-ATA, 5-Iodo-Indirubin-3′-monoxime, 9-Cyanopaullone, Aloisine A,Alsterpaullone 2-Cyanoethyl, alvocidib (Sanofi), AM-5992 (Amgen),Aminopurvalanol A, Arcyriaflavin A, AT-7519 (Astex Pharmaceuticals), AZD5438 (CAS #602306-29-6), BMS-265246 (CAS #582315-72-8), BS-181 (CAS#1092443-52-1), Butyrolactone I (CAS #87414-49-1), Cdk/Crk Inhibitor(CAS #784211-09-2), Cdk1/5 Inhibitor (CAS #40254-90-8), Cdk2 InhibitorII (CAS #222035-13-4), Cdk2 Inhibitor IV, NU6140 (CAS #444723-13-1),Cdk4 Inhibitor (CAS #546102-60-7), Cdk4 Inhibitor III (CAS#265312-55-8), Cdk4/6 Inhibitor IV (CAS #359886-84-3), Cdk9 Inhibitor II(CAS #140651-18-9), CGP 74514A, CR8, CYC-065 (Cyclacel), dinaciclib(Ligand), (R)-DRF053 dihydrochloride (CAS #1056016-06-8), Fascaplysin,Flavopiridol, Hygrolidin, Indirubin, LEE-011 (Astex Pharmaceuticals),LY-2835219 (Eli Lilly), milciclib maleate (Nerviano Medical Sciences),MM-D37K (Maxwell Biotech), N9-Isopropyl-olomoucine, NSC 625987 (CAS#141992-47-4), NU2058 (CAS #161058-83-9), NU6102 (CAS #444722-95-6),Olomoucine, ON-108600 (Onconova), ON-123300 (Onconova), Oxindole I,P-1446-05 (Piramal), P-276-00 (Piramal), palbociclib (Pfizer),PHA-767491 (CAS #845714-00-3), PHA-793887 (CAS #718630-59-2), PHA-848125(CAS #802539-81-7), Purvalanol A, Purvalanol B, R547 (CAS #741713-40-6),RO-3306 (CAS #872573-93-8), Roscovitine, SB-1317 (SBIO), SCH 900776 (CAS#891494-63-6), SEL-120 (Selvita), seliciclib (Cyclacel), SNS-032 (CAS#345627-80-7), SU9516 (CAS #377090-84-1), WHI-P180 (CAS #211555-08-7),pharmaceutically acceptable salts thereof, and combinations thereof.Preferably, the CDK inhibitor is selected from the group consisting ofdinaciclib, palbociclib, pharmaceutically acceptable salts thereof, andcombinations thereof.

As used herein, a “poly ADP ribose polymerase (PARP) inhibitor” is asubstance that decreases the expression or activity of poly ADP ribosepolymerases (PARPs) or downstream proteins. Non-limiting examples ofpoly ADP ribose polymerase (PARP) inhibitors of the present inventioninclude PF01367338 (Pfizer, New York, N.Y.), olaparib (AstraZeneca,United Kingdom), iniparib (Sanofi-Aventis, Paris, France), veliparib(Abbott Laboratories, Abbott Park, Ill.), MK 4827 (Merck, White HouseStation, N.J.), CEP 9722 (Teva Pharmaceuticals, Israel), LT-673(Biomarin, San Rafael, Calif.), and BSI 401 (Sanofi-Aventis, Paris,France), pharmaceutically acceptable salts thereof, and combinationsthereof.

As used herein, “immunotherapeutic agent” means any anti-cancer agentthat is compatible with the solid forms of the present invention andthat uses a substance that alters the immune response by augmenting orreducing the ability of the immune system to produce antibodies orsensitized cells that recognize and react with the antigen thatinitiated their production. Immunotherapeutic agents may be recombinant,synthetic, or natural preparations and include cytokines,corticosteroids, cytotoxic agents, thymosin, and immunoglobulins. Someimmunotherapeutic agents are naturally present in the body, and certainof these are available in pharmacologic preparations. Examples ofimmunotherapeutic agents include, but are not limited to, granulocytecolony-stimulating factor (G-CSF), interferons, imiquimod and cellularmembrane fractions from bacteria, IL-2, IL-7, IL-12, CCL3, CCL26, CXCL7,and synthetic cytosine phosphate-guanosine (CpG).

In one preferred embodiment, the immunotherapeutic agent is an immunecheckpoint inhibitor. As used herein, an “immune checkpoint inhibitor”means a substance that blocks the activity of molecules involved inattenuating the immune response. Such molecules include, for example,cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed celldeath protein 1 (PD-1). Immune checkpoint inhibitors of the presentinvention include, but are not limited to, ipilimumab (Bristol-MyersSquibb), tremelimumab (Pfizer), MDX-1106 (Medarex, Inc.), MK3475(Merck), CT-011 (CureTech, Ltd.), AMP-224 (AmpImmune), MDX-1105(Medarex, Inc.), IMP321 (Immutep S.A.), and MGA271 (Macrogenics).

In the present invention, the term “radionuclide” means a radioactivesubstance administered to the patient, e.g., intravenously or orally,after which it penetrates via the patient's normal metabolism into thetarget organ or tissue, where it delivers local radiation for a shorttime. Examples of radionuclides include, but are not limited to, I-125,At-211, Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re-188, In-114m, andY-90.

In the present invention, the term “photoactive therapeutic agent” meanscompounds and compositions that become active upon exposure to light.Certain examples of photoactive therapeutic agents are disclosed, e.g.,in U.S. Patent Application Serial No. 2011/0152230 A1, “PhotoactiveMetal Nitrosyls For Blood Pressure Regulation And Cancer Therapy.”

In the present invention, the term “radiosensitizing agent” means acompound that makes tumor cells more sensitive to radiation therapy.Examples of radiosensitizing agents include misonidazole, metronidazole,tirapazamine, and trans sodium crocetinate.

In the present invention, an “effective amount” or a “therapeuticallyeffective amount” of one or more of the solid forms of the presentinvention or another anti-cancer agent of the invention, including thepharmaceutical compositions containing same, is an amount of such solidform or composition that is sufficient to effect beneficial or desiredresults as described herein when administered to a subject. Effectivedosage forms, modes of administration, and dosage amounts may bedetermined empirically, and making such determinations is within theskill of the art. It is understood by those skilled in the art that thedosage amount will vary with the route of administration, the rate ofexcretion, the duration of the treatment, the identity of any otherdrugs being administered, the age, size, and species of subject, e.g.,human patient, and like factors well known in the arts of medicine andveterinary medicine. In general, a suitable dose of one or more of thesolid forms of the present invention or a pharmaceutical compositionaccording to the invention will be that amount of the solid form orpharmaceutical composition, which is the lowest dose effective toproduce the desired effect. The effective dose of a solid form orpharmaceutical composition of the present invention may be administeredas two, three, four, five, six or more sub-doses, administeredseparately at appropriate intervals throughout the day.

A suitable, non-limiting example of a dosage of a solid form of thepresent invention or another anti-cancer agent disclosed herein is fromabout 1 mg/kg to about 2400 mg/kg per day, such as from about 1 mg/kg toabout 1200 mg/kg per day, 75 mg/kg per day to about 300 mg/kg per day,including from about 1 mg/kg to about 100 mg/kg per day. Otherrepresentative dosages of such agents include about 1 mg/kg, 5 mg/kg, 10mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg,400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, 1000mg/kg, 1100 mg/kg, 1200 mg/kg, 1300 mg/kg, 1400 mg/kg, 1500 mg/kg, 1600mg/kg, 1700 mg/kg, 1800 mg/kg, 1900 mg/kg, 2000 mg/kg, 2100 mg/kg, 2200mg/kg, and 2300 mg/kg per day. The effective dose of a solid form of thepresent invention or other anti-cancer agents disclosed herein may beadministered as two, three, four, five, six or more sub-doses,administered separately at appropriate intervals throughout the day.

The solid form of the present invention or other anti-cancer agents orpharmaceutical compositions containing same of the present invention maybe administered in any desired and effective manner: for oral ingestion,or as an ointment or drop for local administration to the eyes, or forparenteral or other administration in any appropriate manner such asintraperitoneal, subcutaneous, topical, intradermal, inhalation,intrapulmonary, rectal, vaginal, sublingual, intramuscular, intravenous,intraarterial, intrathecal, or intralymphatic. Further, the solid formof the present invention or other anti-cancer agents or pharmaceuticalcompositions containing same of the present invention may beadministered in conjunction with other treatments. The solid form of thepresent invention or other anti-cancer agents or the pharmaceuticalcompositions of the present invention may be encapsulated or otherwiseprotected against gastric or other secretions, if desired.

The pharmaceutical compositions of the invention may comprise one ormore active ingredients, e.g., one or more solid forms of the presentinvention optionally in combination with other anti-cancer agentsanti-cancer agents, in admixture with one or morepharmaceutically-acceptable diluents or carriers and, optionally, one ormore other compounds, drugs, ingredients and/or materials. Regardless ofthe route of administration selected, the agents/compounds of thepresent invention are formulated into pharmaceutically-acceptable dosageforms by conventional methods known to those of skill in the art. See,e.g., Remington, The Science and Practice of Pharmacy (21st Edition,Lippincott Williams and Wilkins, Philadelphia, Pa.).

Pharmaceutically acceptable diluents or carriers are well known in theart (see, e.g., Remington, The Science and Practice of Pharmacy (21stEdition, Lippincott Williams and Wilkins, Philadelphia, Pa.) and TheNational Formulary (American Pharmaceutical Association, Washington,D.C.)) and include sugars (e.g., lactose, sucrose, mannitol, andsorbitol), starches, cellulose preparations, calcium phosphates (e.g.,dicalcium phosphate, tricalcium phosphate and calcium hydrogenphosphate), sodium citrate, water, aqueous solutions (e.g., saline,sodium chloride injection, Ringer's injection, dextrose injection,dextrose and sodium chloride injection, lactated Ringer's injection),alcohols (e.g., ethyl alcohol, propyl alcohol, and benzyl alcohol),polyols (e.g., glycerol, propylene glycol, and polyethylene glycol),organic esters (e.g., ethyl oleate and tryglycerides), biodegradablepolymers (e.g., polylactide-polyglycolide, poly(orthoesters), andpoly(anhydrides)), elastomeric matrices, liposomes, microspheres, oils(e.g., corn, germ, olive, castor, sesame, cottonseed, and groundnut),cocoa butter, waxes (e.g., suppository waxes), paraffins, silicones,talc, silicylate, etc. Each pharmaceutically acceptable diluent orcarrier used in a pharmaceutical composition of the invention must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the subject. Diluents orcarriers suitable for a selected dosage form and intended route ofadministration are well known in the art, and acceptable diluents orcarriers for a chosen dosage form and method of administration can bedetermined using ordinary skill in the art.

The pharmaceutical compositions of the invention may, optionally,contain additional ingredients and/or materials commonly used inpharmaceutical compositions. These ingredients and materials are wellknown in the art and include (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, suchas carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,hydroxypropylmethyl cellulose, sucrose and acacia; (3) humectants, suchas glycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,sodium starch glycolate, cross-linked sodium carboxymethyl cellulose andsodium carbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,and sodium lauryl sulfate; (10) suspending agents, such as ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth; (11) buffering agents; (12) excipients, such as lactose,milk sugars, polyethylene glycols, animal and vegetable fats, oils,waxes, paraffins, cocoa butter, starches, tragacanth, cellulosederivatives, polyethylene glycol, silicones, bentonites, silicic acid,talc, salicylate, zinc oxide, aluminum hydroxide, calcium silicates, andpolyamide powder; (13) inert diluents, such as water or other solvents;(14) preservatives; (15) surface-active agents; (16) dispersing agents;(17) control-release or absorption-delaying agents, such ashydroxypropylmethyl cellulose, other polymer matrices, biodegradablepolymers, liposomes, microspheres, aluminum monostearate, gelatin, andwaxes; (18) opacifying agents; (19) adjuvants; (20) wetting agents; (21)emulsifying and suspending agents; (22), solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan; (23)propellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane; (24) antioxidants; (25) agentswhich render the formulation isotonic with the blood of the intendedrecipient, such as sugars and sodium chloride; (26) thickening agents;(27) coating materials, such as lecithin; and (28) sweetening,flavoring, coloring, perfuming and preservative agents. Each suchingredient or material must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the subject. Ingredients and materials suitable for aselected dosage form and intended route of administration are well knownin the art, and acceptable ingredients and materials for a chosen dosageform and method of administration may be determined using ordinary skillin the art.

The pharmaceutical compositions of the present invention suitable fororal administration may be in the form of capsules, cachets, pills,tablets, powders, granules, a solution or a suspension in an aqueous ornon-aqueous liquid, an oil-in-water or water-in-oil liquid emulsion, anelixir or syrup, a pastille, a bolus, an electuary or a paste. Theseformulations may be prepared by methods known in the art, e.g., by meansof conventional pan-coating, mixing, granulation or lyophilizationprocesses.

Solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like) may be prepared, e.g., bymixing the active ingredient(s) with one or morepharmaceutically-acceptable diluents or carriers and, optionally, one ormore fillers, extenders, binders, humectants, disintegrating agents,solution retarding agents, absorption accelerators, wetting agents,absorbents, lubricants, and/or coloring agents. Solid compositions of asimilar type may be employed as fillers in soft and hard-filled gelatincapsules using a suitable excipient. A tablet may be made by compressionor molding, optionally with one or more accessory ingredients.Compressed tablets may be prepared using a suitable binder, lubricant,inert diluent, preservative, disintegrant, surface-active or dispersingagent. Molded tablets may be made by molding in a suitable machine. Thetablets, and other solid dosage forms, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient therein.They may be sterilized by, for example, filtration through abacteria-retaining filter. These compositions may also optionallycontain opacifying agents and may be of a composition such that theyrelease the active ingredient only, or preferentially, in a certainportion of the gastrointestinal tract, optionally, in a delayed manner.The active ingredient can also be in microencapsulated form.

Liquid dosage forms for oral administration includepharmaceutically-acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. The liquid dosage forms may containsuitable inert diluents commonly used in the art. Besides inertdiluents, the oral compositions may also include adjuvants, such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents. Suspensions maycontain suspending agents.

The pharmaceutical compositions of the present invention for rectal orvaginal administration may be presented as a suppository, which may beprepared by mixing one or more active ingredient(s) with one or moresuitable nonirritating diluents or carriers which are solid at roomtemperature, but liquid at body temperature and, therefore, will melt inthe rectum or vaginal cavity and release the active compound. Thepharmaceutical compositions of the present invention which are suitablefor vaginal administration also include pessaries, tampons, creams,gels, pastes, foams or spray formulations containing suchpharmaceutically-acceptable diluents or carriers as are known in the artto be appropriate.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches, drops and inhalants. The active agent(s)/compound(s), includingthe solid forms of the present invention, may be mixed under sterileconditions with a suitable pharmaceutically-acceptable diluent orcarrier. The ointments, pastes, creams and gels may contain excipients.Powders and sprays may contain excipients and propellants.

The pharmaceutical compositions of the present invention suitable forparenteral administrations may comprise one or more agent(s)/compound(s)in combination with one or more pharmaceutically-acceptable sterileisotonic aqueous or non-aqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsuitable antioxidants, buffers, solutes which render the formulationisotonic with the blood of the intended recipient, or suspending orthickening agents. Proper fluidity can be maintained, for example, bythe use of coating materials, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.These pharmaceutical compositions may also contain suitable adjuvants,such as wetting agents, emulsifying agents and dispersing agents. It mayalso be desirable to include isotonic agents. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption.

In some cases, in order to prolong the effect of a drug (e.g.,pharmaceutical formulation), it is desirable to slow its absorption fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material havingpoor water solubility.

The rate of absorption of the active agent/drug, including the solidforms of the present invention, then depends upon its rate ofdissolution which, in turn, may depend upon crystal size and crystallineform. Alternatively, delayed absorption of a parenterally-administeredagent/drug may be accomplished by dissolving or suspending the activeagent/drug in an oil vehicle. Injectable depot forms may be made byforming microencapsule matrices of the active ingredient inbiodegradable polymers. Depending on the ratio of the active ingredientto polymer, and the nature of the particular polymer employed, the rateof active ingredient release can be controlled. Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue. The injectablematerials can be sterilized for example, by filtration through abacterial-retaining filter.

The formulations may be present in unit-dose or multi-dose sealedcontainers, for example, ampules and vials, and may be stored in alyophilized condition requiring only the addition of the sterile liquiddiluent or carrier, for example water for injection, immediately priorto use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the typedescribed above.

The following examples are provided to further illustrate the compounds,compositions and methods of the present invention. These examples areillustrative only and are not intended to limit the scope of theinvention in any way.

EXAMPLES Example 1 Experimental Methods X-Ray Powder Diffraction (XRPD)

Transmission mode XRPD patterns were collected using an incident beam ofCu radiation produced using a fine-focus source. An elliptically gradedmultilayer mirror was used to focus Cu Kα X-ray radiation through thespecimen and onto the detector. Prior to the analysis, a siliconspecimen (NIST SRM 640d) was analyzed to verify that the observedposition of the Si 111 peak was consistent with the NIST-certifiedposition. A specimen of the sample was sandwiched between 3-μm-thickfilms and analyzed in transmission geometry. A beam-stop, shortantiscatter extension, and antiscatter knife edge were used to minimizethe background generated by air. Soller slits for the incident anddiffracted beams were used to minimize broadening from axial divergence.Diffraction patterns were collected using a scanning position-sensitivedetector located 240 mm from the specimen. Preferred orientation andparticle static effects were not assessed.

Reflection mode XRPD patterns were collected using an incident beam ofCu Kα radiation produced using a fine-focus source and a nickel filter.The diffractometer was configured using the symmetric Bragg-Brentanogeometry. Prior to the analysis, a silicon specimen (NIST SRM 640d) wasanalyzed to verify that the observed position of the Si 111 peak wasconsistent with the NIST-certified position. A specimen of the samplewas prepared as a thin, circular layer centered on a siliconzero-background substrate. Antiscatter slits (SS) were used to minimizethe background generated by air. Soller slits for the incident anddiffracted beams were used to minimize broadening from axial divergence.Diffraction patterns were collected using a scanning position-sensitivedetector located 240 mm from the sample. Preferred orientation andparticle static effects were not assessed.

Under most circumstances, peaks within the range of up to about 30° 2θwere selected. The location of the peaks along the x-axis (° 2θ) wererounded to one significant figure after the decimal point. Peak positionvariabilities are given to within ±0.2° 2θ based upon recommendationsoutlined in the USP discussion of variability in X-ray powderdiffraction. The accuracy and precision associated with any particularmeasurement was not determined. Moreover, third party measurements onindependently prepared samples on different instruments may lead tovariability which is greater than ±0.2° 2θ. Per USP guidelines, variablehydrates and solvates may display peak variances greater than 0.2° 2θand therefore peak variances of 0.2° 2θ are not applicable to thesematerials. For d-space listings, the wavelength used to calculated-spacings was 1.5405929 Å, the Cu-Kα1 wavelength. Variabilityassociated with d-spacing estimates was calculated from the USPrecommendation, at each d-spacing, and provided in the respective datatables.

Fourier Transform Infrared (FT-IR) Spectroscopy

FT-IR spectra were acquired using a Fourier transform infraredspectrophotometer equipped with a mid/far IR source, an extended rangepotassium bromide (KBr) beamsplitter, and a deuterated triglycinesulfate (DTGS) detector. Wavelength verification was performed usingNIST SRM 1921b (polystyrene). An attenuated total reflectance (ATR)accessory with a germanium (Ge) crystal was used for data acquisition.256 co-added scans were collected at a spectral resolution of 2 cm⁻¹. Abackground data set was acquired with a clean Ge crystal. A Log 1/R(R=reflectance) spectrum was obtained by taking a ratio of these twodata sets against each other. Peak picking was performed using anabsolute threshold near the baseline and a sensitivity of 75.

Differential Scanning Calorimetry (DSC)

DSC analysis was performed using a differential scanning calorimeter.Temperature calibration was performed using NIST-traceable indium metal.The sample was placed into an aluminum DSC pan, covered with a lid, andthe weight was accurately recorded. A weighed aluminum T0HSMP panconfigured as the sample pan was placed on the reference side of thecell. Reported temperatures are rounded to 1 degree unless specifiedotherwise.

Raman Spectroscopy

Raman spectroscopy was performed using a dispersive RamanRXN3 (KaiserOptical Systems Inc., Ann Arbor, Mich.) for in-situ reaction monitoring.The RamanRXN3 system uses an excitation wavelength of 785 nm, with anexternal cavity-stabilized, diode laser. All spectra were acquired usinga ¼″ immersion optics probe with approximately 103 mW of laser power atthe tip of the probe. The spectra were collected using an exposure timeof 5 up to 15 seconds and with 5 spectrum accumulations. Wavelength andlaser wavelength calibration were performed using an internal neonstandard, and diamond Raman shift standard, respectively. The intensitycalibration was performed using a Kaiser Raman calibration accessory(Kaiser Optical Systems Inc., Ann Arbor, Mich.).

Example 2 Preparation of Crystaline Free Base4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic Acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide free base was preparedaccording to the following synthesis scheme.

In Step 1, a clean and dry 200 L glass-lined reactor was evacuated to≤−0.08 MPa, and then filled with nitrogen to normal pressure threetimes. Anhydrous ethanol (49.90 kg) was charged into the 200 Lglass-lined reactor. ASYM-111606 (Asymchem) (12.70 kg) andisopropylamine (29.00 kg) were added into the mixture in turn. Themixture was heated to 65-75° C. for refluxing. The mixture reacted at65-75° C. After 20 h, the reaction was sampled and analyzed by HPLCevery 4-6 h until the content of ASYM-111606 was 1%. The mixture wascooled to 40-45° C. and was concentrated at ≤45° C. under reducedpressure (≤−0.08 MPa) until 13-26 L remained. The organic phase waswashed with a sodium chloride solution and was stirred for 20-30 min andsettled for 20-30 min before separation. The organic phase wasconcentrated at ≤30° C. under reduced pressure (≤−0.06 MPa) until 13-20L remained. Petroleum ether (8.55 kg) was added into the concentratedmixture. The mixture was transferred into a 20 L rotary evaporator andcontinued concentrating at ≤30° C. under reduced pressure (≤−0.06 MPa)until 13-20 L remained. Then petroleum ether (8.55 kg) was added intothe concentrated mixture. The mixture was cooled to 0-5° C. and stirredfor crystallization. After 1 h, the mixture was sampled and analyzed bywt % every 1-2 h until the wt % of the mother liquor was ≤11% or thechange of the wt % between consecutive samples was ≤1%. The mixture wasfiltered with a 10 L filter flask. The filter cake was sampled andanalyzed for purity by HPLC. 10.50 kg of product was recovered as abrownish yellow solid at 99.39% purity.

In Step 2, a clean and dry 300 L glass-lined reactor was evacuated to≤−0.08 MPa, and then filled with nitrogen to normal pressure threetimes. Glycol dimethyl ether (73.10 kg) was charged into the 300 Lglass-lined reactor at 20-30° C. ASYM-112060 (Asymchem) (10.46 kg) andASYM-111938 (Asymchem) (12.34 kg, 11.64 kg after corrected) were addedinto the mixture in turn under the protection of nitrogen. Maintainingthe temperature at 20-30° C., purified water (10.50 kg) and anhydroussodium carbonate (5.67 kg) were added into the mixture. Palladiumacetate (0.239 kg) and tricyclohexylphosphonium tetrafluoroborate (0.522kg) were added into the mixture under the protection of nitrogen. Afteraddition, the mixture was evacuated to ≤−0.06 MPa, and then filled withnitrogen to normal pressure. This was repeated for ten times untilresidual oxygen was ≤300 ppm. The mixture was heated to 75-85° C. forrefluxing. The mixture reacted at 75-85° C. After 4 h, the mixture wassampled and analyzed by HPLC every 2-3 h for content of ASYM-112060. Thecontent of ASYM-112060 was 6.18%, so additional ASYM-111938 (0.72 kg)was added and continued reaction until the content of ASYM-112060 was≤3%. The mixture was cooled to 25-35° C. and filtered with a 30 Lstainless steel vacuum filter. The filter cake was soaked and washedtwice with THF (14.10 kg). The filtrate and washing liquor were combinedand concentrated at ≤50° C. under reduced pressure (≤−0.08 MPa) until10-15 L remained. The mixture was cooled to 15-25° C. Methanol (11.05kg) was added into the concentrated mixture. Then the mixture wasstirred for crystallization. After 2 h, the mixture was sampled andanalyzed by HPLC every 2-4 h until the wt % of the mother liquor was≤2%. The mixture was filtered with a 30 L stainless steel vacuum filter.The filter cake was soaked and washed twice with methanol (8.30 kg). Thefilter cake was transferred into a 50 L plastic drum. Then ethyl acetate(7.10 kg) and petroleum ether (46.30 kg) were added into the drum. Themixture was stirred for 1.5-2 h and then filtered with a nutsche filter.The filter cake was soaked and washed with petroleum ether (20.50 kg).The filter cake was dried in the nutsche filter under nitrogen at 30-40°C. After 8 h, the solid was sampled and Karl Fischer (KF) analysis wasperformed in intervals of 4-8 h to monitor the drying process. Dryingwas completed when the KF result was 1.0% water. During drying, thesolid was turned over and mixed every 4-6 h. 12.15 kg of product wasrecovered as a brownish yellow solid at 98.32% purity.

In Step 3, a clean and dry 300 L glass-lined reactor was evacuated to≤−0.08 MPa, and then filled with nitrogen to normal pressure threetimes. THF (62.58 kg) was charged into the 300 L glass-lined reactor at15-30° C. Then the stirrer was started. ASYM-112393 (12.00 kg, 11.70 kgafter corrected) was added into the mixture. The mixture was stirreduntil the solid dissolved completely. Maintaining the temperature at15-30° C., a lithium hydroxide solution which was prepared with lithiumhydroxide monohydrate (5.50 kg) in purified water (70.28 kg) was addedinto the mixture. Then diethylamine (3.86 kg) was added. The mixture washeated to 60-70° C. for refluxing. The mixture reacted at 60-70° C.After 30 h, the reaction was sampled and analyzed by HPLC every 4-6 huntil the content of intermediate at relative retention time(RRT)=1.39-1.44 was ≤1% and the content of ASYM-112393 was ≤1%. HPLCconditions for this analysis are set forth in Table 1.

TABLE 1 HPLC Parameters Column: ACE 3 C18, 4.6 × 150 mm, (ACE-111-1546)Column 30° C. Temperature: Flow rate 1.1 mL/min Injection 10 μL Volume:Mobile Phase A: 0.05% TFA in water (v/v) Mobile Phase B: 0.05% TFA inAcetonitrile (v/v) T (min): B % Gradient Table: 0.0 5 4.0 20 14.0 8514.1 5 18.5 5 Detection: UV at 215 nm Run time 18.5 min

The mixture was cooled to 25-35° C. and MTBE (25.97 kg) was added intothe mixture. The mixture was stirred for 20-30 min and filtered via anin-line fluid filter. The filtrate was transferred into a 300 Lglass-lined reactor and settled for 20-30 min before separation. The pHof the obtained aqueous phase was adjusted with a 6 N hydrochloric acidsolution which was prepared from concentrated hydrochloric acid (14.86kg) in purified water (10.88 kg) at the rate of 5-8 kg/h at 15-25° C.until the pH was 1-2. The pH of the mixture was adjusted again with asaturated sodium carbonate solution which was prepared from sodiumcarbonate (5.03 kg) in purified water (23.56 kg) at the rate of 3-5 kg/hat 15-25° C. until the pH was 6.4-6.7. Then the pH of the mixture wasadjusted with a hydrochloric acid solution which was prepared fromconcentrated hydrochloric acid (1.09 kg) in purified water (0.80 kg)until the pH was 6.2-6.4. The mixture was filtered with a nutschefilter. The filter cake was transferred into a 300 L glass-lined reactorand purified water (117.00 kg) was added. The mixture was stirred andsampled and analyzed by HPLC until the p-toluenesulfonic acid residue ofthe filter cake was ≤0.5%. Then the mixture was filtered. The filtercake was dried in the tray drier under nitrogen at 55-65° C. untilKF≤10%. The solid and MTBE (8.81 kg) were charged into a 50 L stainlesssteel drum. The mixture was stirred for 1-2 h. The mixture was filteredwith a 30 L stainless steel vacuum filter. The filter cake was dried inthe nutsche filter at 50-60° C. After 8 h, the solid was sampled andanalyzed by KF every 4-8 h until KF≤5%. During drying, the solid wasturned over and mixed every 4-6 h. 6.3 kg of product was recovered as anoff-white solid at 98.07% purity.

In Step 4, a dry and clean 50 L flask was purged with nitrogen for 20min. DMF (30.20 kg) was charged into the 50 L flask reactor. Then thestirrer was started. Maintaining the temperature at 15-25° C.,ASYM-112394 (3.22 kg, 2.76 kg after corrected) was added into themixture. The mixture was stirred until the solid dissolved completely.The mixture was cooled to −10 to −20° C. and 1-hydroxybenzotriazolehydrate (2.10 kg) was added into the mixture at −10 to −20° C. Then EDCl(2.41 kg) was added into the mixture in five portions at an interval ofabout 5-10 min. The mixture was cooled to −20 to −30° C. and ASYM-111888(Asymchem) (1.96 kg) was added into the mixture at −20 to −30° C. ThenDIEA (1.77 kg) was added into the mixture at the rate of 3-4 kg/h. Themixture was heated to 15-25° C. at the rate of 5-10° C./h. The mixturewas reacted at 15-25° C. After 6-8 h, the mixture was sampled andanalyzed by HPLC every 2-4 h until the content of ASYM-112394 was ≤2%.The mixture was cooled to 0-10° C. and the reaction mixture was quenchedwith a solution which was prepared from ethyl acetate (28.80 kg) inpurified water (12.80 kg) at 0-10° C. The mixture was extracted threetimes with ethyl acetate (28.80 kg). For each extraction the mixture wasstirred for 20-30 min and settled for 20-30 min before separation. Theorganic phases were combined and washed twice with purified water (12.80kg). The mixture was stirred for 20-30 min and settled for 20-30 minbefore separation for each time. Then the obtained organic phase wasfiltered through an in-line fluid filter. The filtrate was transferredinto a 300 L glass-lined reactor. The mixture was washed twice with a 5%acetic acid solution, which was prepared from acetic acid (2.24 kg) inpurified water (42.50 kg). The solution was added at the rate of 10-20kg/h. The organic phase was washed twice with a sodium carbonatesolution, which was prepared from sodium carbonate (9.41 kg) in purifiedwater (48.00 kg). The organic phase was washed twice with a sodiumchloride solution, which was prepared from sodium chloride (16.00 kg) inpurified water (44.80 kg). The organic phase was transferred into a 300L glass-lined reactor. Anhydrous sodium sulfate (9.70 kg) was added intothe mixture and the mixture was stirred for 2-4 h at 15-30° C. Themixture was filtered with a nutsche filter, which was pre-loaded withabout 1 cm thick silica gel (7.50 kg). The filter cake was soaked andwashed with ethyl acetate (14.40 kg) before filtration. The filtrateswere combined and the combined filtrate was added into a 72 L flaskthrough an in-line fluid filter. The mixture was concentrated at T≤40°C. under reduced pressure (P≤−0.08 MPa) until 3-4 L remained. Then MTBE(4.78 kg) was added into the mixture. The mixture was cooled to 0-10° C.for crystallization with stirring. After 1 h, the mixture was sampledand analyzed by wt % every 1-2 h until the wt % of the mother liquor was55% or the change of wt % between consecutive samples was ≤1%. Themixture was filtered with a vacuum filter flask and the filter cake wasdried in the tray drier under nitrogen at 30-40° C. until KF≤0.5%. 3.55kg of product was recovered as an off-white solid at 100% purity.

The resulting4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide free base was analyzed by XRPD(FIG. 1). Peaks shown in FIG. 1 are listed in Table 2, prominent peaksare listed in Table 3.

TABLE 2 XRPD peaks observed for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide free base. 2θ (°) d space (Å) Intensity (%)  9.1 ±0.2 9.690 ± 0.212 12 10.0 ± 0.2 8.869 ± 0.178 2 10.2 ± 0.2 8.664 ± 0.1697 11.4 ± 0.2 7.742 ± 0.135 5 12.5 ± 0.2 7.066 ± 0.112 25 12.7 ± 0.26.956 ± 0.109 8 13.3 ± 0.2 6.637 ± 0.099 2 15.2 ± 0.2 5.833 ± 0.076 1515.4 ± 0.2 5.769 ± 0.075 46 16.0 ± 0.2 5.531 ± 0.069 9 17.1 ± 0.2 5.173± 0.060 3 17.6 ± 0.2 5.038 ± 0.057 8 18.2 ± 0.2 4.876 ± 0.053 4 18.8 ±0.2 4.723 ± 0.050 2 19.2 ± 0.2 4.624 ± 0.048 12 19.5 ± 0.2 4.556 ± 0.046100 20.3 ± 0.2 4.381 ± 0.043 14 20.5 ± 0.2 4.327 ± 0.042 12 21.4 ± 0.24.145 ± 0.038 44 21.7 ± 0.2 4.102 ± 0.037 11 21.9 ± 0.2 4.057 ± 0.037 1223.1 ± 0.2 3.847 ± 0.033 13 23.3 ± 0.2 3.812 ± 0.032 25 23.6 ± 0.2 3.774± 0.032 26 24.3 ± 0.2 3.653 ± 0.030 11 25.2 ± 0.2 3.530 ± 0.028 9 25.6 ±0.2 3.476 ± 0.027 2 26.6 ± 0.2 3.355 ± 0.025 3 27.0 ± 0.2 3.297 ± 0.0247 27.7 ± 0.2 3.214 ± 0.023 13 27.9 ± 0.2 3.191 ± 0.022 10 28.2 ± 0.23.159 ± 0.022 3 28.7 ± 0.2 3.106 ± 0.021 9 28.9 ± 0.2 3.083 ± 0.021 429.2 ± 0.2 3.057 ± 0.020 9 30.2 ± 0.2 2.957 ± 0.019 14 30.6 ± 0.2 2.923± 0.019 9

TABLE 3 Prominent XRPD peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide free base. 2θ (°) d space (Å) Intensity (%)  9.1 ±0.2 9.690 ± 0.212 12 12.5 ± 0.2 7.066 ± 0.112 25 15.2 ± 0.2 5.833 ±0.076 15 15.4 ± 0.2 5.769 ± 0.075 46 19.2 ± 0.2 4.624 ± 0.048 12 19.5 ±0.2 4.556 ± 0.046 100 20.3 ± 0.2 4.381 ± 0.043 14 20.5 ± 0.2 4.327 ±0.042 12 21.4 ± 0.2 4.145 ± 0.038 44 21.7 ± 0.2 4.102 ± 0.037 11 21.9 ±0.2 4.057 ± 0.037 12 23.1 ± 0.2 3.847 ± 0.033 13 23.3 ± 0.2 3.812 ±0.032 25 23.6 ± 0.2 3.774 ± 0.032 26 24.3 ± 0.2 3.653 ± 0.030 11 27.7 ±0.2 3.214 ± 0.023 13 27.9 ± 0.2 3.191 ± 0.022 10 30.2 ± 0.2 2.957 ±0.019 14

FT-IR was performed on a sample of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide free base as described inExample 1 (FIG. 2). Observed peaks from FIG. 2 are listed in Table 4.

TABLE 4 Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide free base. Position (cm⁻¹) Intensity 681 0.0174 7120.0025 748 0.0014 783 0.0058 807 0.001 827 0.0082 857 0.0045 878 0.00069897 0.00067 916 0.00056 932 0.0008 996 0.0004 1040 0.00074 1080 0.00691101 0.00081 1126 0.00096 1145 0.0014 1170 0.0027 1197 0.0011 12080.0028 1235 0.0013 1255 0.0015 1268 0.0021 1294 0.0013 1350 0.0018 13640.002 1385 0.00077 1398 0.00077 1439 0.0017 1451 0.0014 1466 0.0019 14870.0089 1504 0.0033 1523 0.0065 1533 0.0063 1568 0.0021 1603 0.0108 16290.0062 2927 0.00024 2974 0.00028 3235 0.00052 3405 0.00026

DSC was performed on a sample of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide free base as described inExample 1 (FIG. 3) and showed an endotherm having an onset temperatureof approximately 184° C.

Example 3A Preparation of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic Acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C was prepared from4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide free base as follows.ASYM-111935 (10.4 kg) was added to a stirred mixture of anhydrousethanol (73.9 kg), methanol (4.1 kg) and isopropanol (4.1 kg). Themixture was heated to 70-75° C. and stirred until all the solidsdissolved. Anhydrous HCl (37 wt %, 1.1 eq) in a mixture ofethanol/methanol/isopropanol (90:5:5) was added and the mixturemaintained at 70-75° C. for 2 hours after the addition was completed.The mixture was then cooled to 15-25° C. at a rate of 5-15° C. per hourand stirred at this temperature until the desired polymorphic purity wasreached. The end point of the crystallization/polymorph conversion wasdetermined by the absence of an XRPD peak at about 10.5° 2θ in threesuccessive samples.

The mixture was then filtered and washed successively with apre-prepared solution of anhydrous ethanol (14.8 kg), methanol (0.8 kg)and isopropanol (0.8 kg), followed by MTBE (2×21 kg). Avoidance of delayin the washing of the filter cake is preferable because the polymorphmay be unstable in the wet filter cake in the presence of reagentalcohol and improved stability was observed after the MTBE wash has beenperformed. The wet filter cake was then dried in a heated filter funnelor a tray drier at 40-50° C. until dry. Typical yields were about85-90%.

Example 3B Alternative Preparation of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic Acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C was also prepared from4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide free base as follows. A dry andclean 72 L flask was purged with nitrogen for 20 min. Anhydrous ethanol(21.35 kg) methanol (1.17 kg) and isopropanol (1.19 kg) were chargedinto the 72 L flask at 15-25° C. and the mixture was stirred for 20-30min. ASYM-111935 (3.01 kg) was added into the mixture and heated to70-75° C. at the rate of 15-25° C./h and stirred until the soliddissolved completely.

An alcohol/HCl solution was prepared as follows. Anhydrous ethanol(1.500 kg) methanol (0.088 kg) and isopropanol (0.087 kg) were chargedinto a 5 L flask at 15-25° C. and the mixture was stirred for 20-30 min.The mixture was bubbled with hydrogen chloride through a dip tube understirring at 10-25° C. After 2 h, the mixture was sampled and analyzedevery 2-4 h until the wt % of hydrogen chloride was ≥35%.

The alcohol/HCl solution (0.519 kg) prepared above was added dropwiseinto the mixture at the rate of 0.5-1.0 kg/h at 70-75° C. Seed crystal(0.009 kg) was added into the mixture and the alcohol/HCl solution(0.173 kg) prepared above was added into the mixture at the rate of0.5-1.0 kg/h at 70-75° C. After addition, the mixture was stirred for1-2 h at 70-75° C. The mixture was cooled to 15-25° C. at the rate of5-15° C./h and stirred for 4-6 h. The mixture was heated to 70-75° C. atthe rate of 15-25° C./h and stirred for 8-10 h at 70-75° C. The mixturewas cooled to 15-25° C. at the rate of 5-15° C./h and stirred for 4-6 h.The mixture was filtered with a vacuum filter flask. The filter cake wassoaked and rinsed with a solution which was prepared from anhydrousethanol (4.25 kg) and methanol (0.24 kg) and isopropanol (0.24 kg)before filtration. The filter cake was dried in a drying room undernitrogen at 40-50° C. until the ethanol residue was <0.5% and methanolresidue was <0.3% and isopropanol residue was <0.3%. 2.89 kg of productwas recovered as a white solid at 99.97% purity.

The resulting4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C was analyzed by XRPD(FIG. 4). Peaks shown in FIG. 4 are listed in Table 5, prominent peaksare listed in Table 6.

TABLE 5 XRPD peaks observed for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C. 2θ (°) d space (Å) Intensity (%)  6.1 ± 0.214.436 ± 0.472  17  6.7 ± 0.2 13.099 ± 0.388  61  8.6 ± 0.2 10.287 ±0.239  5 10.8 ± 0.2 8.196 ± 0.152 5 11.0 ± 0.2 8.039 ± 0.146 15 12.1 ±0.2 7.335 ± 0.121 15 12.4 ± 0.2 7.108 ± 0.114 6 13.5 ± 0.2 6.533 ± 0.0968 13.7 ± 0.2 6.467 ± 0.094 10 15.2 ± 0.2 5.828 ± 0.076 38 16.5 ± 0.25.363 ± 0.064 18 16.9 ± 0.2 5.258 ± 0.062 7 17.2 ± 0.2 5.139 ± 0.059 517.6 ± 0.2 5.023 ± 0.056 59 17.9 ± 0.2 4.949 ± 0.055 37 18.4 ± 0.2 4.818± 0.052 32 18.7 ± 0.2 4.743 ± 0.050 13 19.0 ± 0.2 4.671 ± 0.049 4 19.2 ±0.2 4.628 ± 0.048 4 19.6 ± 0.2 4.529 ± 0.046 14 19.9 ± 0.2 4.450 ± 0.044100 20.4 ± 0.2 4.354 ± 0.042 18 20.6 ± 0.2 4.318 ± 0.042 28 20.8 ± 0.24.272 ± 0.041 52 21.5 ± 0.2 4.122 ± 0.038 28 22.1 ± 0.2 4.016 ± 0.036 422.6 ± 0.2 3.935 ± 0.034 28 22.7 ± 0.2 3.923 ± 0.034 27 23.5 ± 0.2 3.785± 0.032 43 24.0 ± 0.2 3.704 ± 0.030 29 24.3 ± 0.2 3.664 ± 0.030 12 24.5± 0.2 3.634 ± 0.029 8 24.9 ± 0.2 3.573 ± 0.028 56 25.4 ± 0.2 3.498 ±0.027 60 25.7 ± 0.2 3.467 ± 0.027 37 26.0 ± 0.2 3.424 ± 0.026 6 26.4 ±0.2 3.375 ± 0.025 8 27.7 ± 0.2 3.224 ± 0.023 22 28.0 ± 0.2 3.182 ± 0.02211 28.3 ± 0.2 3.147 ± 0.022 8 29.2 ± 0.2 3.056 ± 0.020 4 29.6 ± 0.23.020 ± 0.020 7 29.9 ± 0.2 2.983 ± 0.019 28 30.2 ± 0.2 2.957 ± 0.019 10

TABLE 6 Prominent XRPD peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C. 2θ (°) d space (Å) Intensity (%)  6.1 ± 0.214.436 ± 0.472  17  6.7 ± 0.2 13.099 ± 0.388  61 11.0 ± 0.2 8.039 ±0.146 15 12.1 ± 0.2 7.335 ± 0.121 15 13.7 ± 0.2 6.467 ± 0.094 10 15.2 ±0.2 5.828 ± 0.076 38 16.5 ± 0.2 5.363 ± 0.064 18 17.6 ± 0.2 5.023 ±0.056 59 17.9 ± 0.2 4.949 ± 0.055 37 18.4 ± 0.2 4.818 ± 0.052 32 18.7 ±0.2 4.743 ± 0.050 13 19.6 ± 0.2 4.529 ± 0.046 14 19.9 ± 0.2 4.450 ±0.044 100 20.4 ± 0.2 4.354 ± 0.042 18 20.6 ± 0.2 4.318 ± 0.042 28 20.8 ±0.2 4.272 ± 0.041 52 21.5 ± 0.2 4.122 ± 0.038 28 22.6 ± 0.2 3.935 ±0.034 28 22.7 ± 0.2 3.923 ± 0.034 27 23.5 ± 0.2 3.785 ± 0.032 43 24.0 ±0.2 3.704 ± 0.030 29 24.3 ± 0.2 3.664 ± 0.030 12 24.9 ± 0.2 3.573 ±0.028 56 25.4 ± 0.2 3.498 ± 0.027 60 25.7 ± 0.2 3.467 ± 0.027 37 27.7 ±0.2 3.224 ± 0.023 22 28.0 ± 0.2 3.182 ± 0.022 11 29.9 ± 0.2 2.983 ±0.019 28 30.2 ± 0.2 2.957 ± 0.019 10

FT-IR was performed on a sample of Form C as described in Example 1(FIG. 5). Observed peaks from FIG. 5 are listed in Table 7.

TABLE 7 Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C. Position (cm⁻¹) Intensity 680 0.0389 6940.0737 705 0.0203 723 0.0273 728 0.0245 742 0.0263 771 0.0449 785 0.0527845 0.0479 865 0.0128 879 0.0232 922 0.0112 946 0.0275 958 0.011 9850.0119 1000 0.0124 1076 0.0649 1107 0.0183 1129 0.0245 1141 0.0322 11770.018 1219 0.0554 1246 0.0238 1282 0.0279 1310 0.0342 1324 0.0179 13440.0144 1376 0.0239 1380 0.024 1389 0.0204 1413 0.0196 1436 0.0324 14720.0279 1498 0.0254 1523 0.0543 1551 0.027 1574 0.0371 1610 0.0697 16430.0865 2952 0.0153 2977 0.0167 3057 0.015 3178 0.0147 3229 0.0162 32940.0171 3369 0.0161

DSC was performed on a sample of Form C as described in Example 1 (FIG.6) and showed a prominent endotherm having an onset temperature ofapproximately 239° C.

Example 4 Preparation of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic Acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C was dissolved inmethanol at 60° C. resulting in a clear solution. The sample was slowcooled from 60° C. to ambient temperature followed by fast evaporation.4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A was formed as whitesolids/needles.

Alternatively,4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C was dissolved in ethanolat 60° C. resulting in a clear solution. The sample was slow cooled from60° C. to ambient temperature followed by fast evaporation.4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A was formed as whitesolids/needles.

Alternatively,4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form C was prepared as a slurryin ethanol resulting in a white suspension. The ethanol slurry wasmaintained at ambient temperature for 7 days.4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A was formed as white tinyspecks.

The resulting4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A was analyzed by XRPD(FIG. 7). Peaks shown in FIG. 7 are listed in Table 8, prominent peaksare listed in Table 9.

TABLE 8 XRPD peaks observed for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A. 2θ (°) d space (Å) Intensity (%)  5.8 ± 0.215.175 ± 0.521  20  5.9 ± 0.2 14.992 ± 0.509  22  6.2 ± 0.2 14.250 ±0.459  76 10.5 ± 0.2 8.418 ± 0.160 100 11.7 ± 0.2 7.571 ± 0.129 6 11.8 ±0.2 7.474 ± 0.126 11 12.4 ± 0.2 7.114 ± 0.114 20 15.3 ± 0.2 5.772 ±0.075 7 15.9 ± 0.2 5.587 ± 0.070 17 16.1 ± 0.2 5.506 ± 0.068 9 16.3 ±0.2 5.440 ± 0.066 6 16.4 ± 0.2 5.393 ± 0.065 5 17.6 ± 0.2 5.048 ± 0.05749 17.8 ± 0.2 4.980 ± 0.056 21 18.7 ± 0.2 4.740 ± 0.050 9 19.8 ± 0.24.478 ± 0.045 6 20.0 ± 0.2 4.427 ± 0.044 25 20.4 ± 0.2 4.345 ± 0.042 1020.7 ± 0.2 4.291 ± 0.041 8 20.9 ± 0.2 4.249 ± 0.040 7 21.1 ± 0.2 4.209 ±0.039 11 21.4 ± 0.2 4.153 ± 0.038 23 21.9 ± 0.2 4.052 ± 0.037 17 22.4 ±0.2 3.963 ± 0.035 82 23.1 ± 0.2 3.854 ± 0.033 11 23.5 ± 0.2 3.790 ±0.032 7 24.0 ± 0.2 3.702 ± 0.030 47 24.2 ± 0.2 3.677 ± 0.030 23 24.9 ±0.2 3.570 ± 0.028 100 25.3 ± 0.2 3.523 ± 0.027 19 25.7 ± 0.2 3.470 ±0.027 27 26.4 ± 0.2 3.370 ± 0.025 10 26.9 ± 0.2 3.317 ± 0.024 17 26.9 ±0.2 3.307 ± 0.024 16 27.2 ± 0.2 3.281 ± 0.024 13 27.3 ± 0.2 3.260 ±0.023 11 27.8 ± 0.2 3.208 ± 0.023 9 28.1 ± 0.2 3.178 ± 0.022 29 28.5 ±0.2 3.130 ± 0.022 43 29.8 ± 0.2 2.999 ± 0.020 32

TABLE 9 Prominent XRPD peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A. 2θ (°) d space (Å) Intensity (%)  5.8 ± 0.215.175 ± 0.521  20  5.9 ± 0.2 14.992 ± 0.509  22  6.2 ± 0.2 14.250 ±0.459  76 10.5 ± 0.2 8.418 ± 0.160 100 11.8 ± 0.2 7.474 ± 0.126 11 12.4± 0.2 7.114 ± 0.114 20 15.9 ± 0.2 5.587 ± 0.070 17 17.6 ± 0.2 5.048 ±0.057 49 17.8 ± 0.2 4.980 ± 0.056 21 20.0 ± 0.2 4.427 ± 0.044 25 20.4 ±0.2 4.345 ± 0.042 10 21.1 ± 0.2 4.209 ± 0.039 11 21.4 ± 0.2 4.153 ±0.038 23 21.9 ± 0.2 4.052 ± 0.037 17 22.4 ± 0.2 3.963 ± 0.035 82 23.1 ±0.2 3.854 ± 0.033 11 24.0 ± 0.2 3.702 ± 0.030 47 24.2 ± 0.2 3.677 ±0.030 23 24.9 ± 0.2 3.570 ± 0.028 100 25.3 ± 0.2 3.523 ± 0.027 19 25.7 ±0.2 3.470 ± 0.027 27 26.4 ± 0.2 3.370 ± 0.025 10 26.9 ± 0.2 3.317 ±0.024 17 26.9 ± 0.2 3.307 ± 0.024 16 27.2 ± 0.2 3.281 ± 0.024 13 27.3 ±0.2 3.260 ± 0.023 11 28.1 ± 0.2 3.178 ± 0.022 29 28.5 ± 0.2 3.130 ±0.022 43 29.8 ± 0.2 2.999 ± 0.020 32

FT-IR was performed on a sample of Form A as described in Example 1(FIG. 8). Observed peaks from FIG. 8 are listed in Table 10.

TABLE 10 Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A. Position (cm⁻¹) Intensity 679 0.0296 6870.0661 689 0.0658 712 0.0619 729 0.0227 742 0.0202 787 0.0614 790 0.0458827 0.04 833 0.0371 844 0.0446 868 0.0259 877 0.0224 892 0.018 920 0.014946 0.0385 979 0.0103 1001 0.0098 1042 0.0228 1068 0.0248 1094 0.02691122 0.0195 1163 0.0564 1192 0.0176 1215 0.0443 1237 0.0651 1284 0.02951309 0.0387 1329 0.0308 1345 0.0262 1383 0.0214 1394 0.0227 1428 0.02881452 0.0369 1462 0.0366 1471 0.0374 1500 0.0496 1537 0.0473 1573 0.0641599 0.0412 1613 0.086 1631 0.0909 1648 0.069 1823 0.0052 2734 0.01932939 0.0157 2972 0.0182 3124 0.0184 3165 0.019 3250 0.0184

DSC was performed on a sample of Form A as described in Example 1 (FIG.9) and showed four endothermic events: melting of water at 0° C.,followed by two broad events having peak maxima at temperatures ofapproximately 61° C. and 136° C. with weight losses of 3.0% and 1.9%,respectively and, finally, an endotherm having an onset temperature ofapproximately 201° C.

Example 5 Preparation of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic Acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form D

A vessel containing4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form A was purged with drynitrogen and relative humidity was monitored. After about 73 minutes therelative humidity had decreased from 36.9% to 1.0%. The resultingmaterial was analyzed and was determined to be a new form, designatedForm D.

In a related experiment, a sample of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form D was, upon sorption ofwater, observed to be Form A. This led to the conclusion that Forms Aand D interconvert reversibly as a function of relative humidity.

A sample of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Form D was analyzed by XRPD(FIG. 10). Peaks shown in FIG. 10 are listed in Table 11, prominentpeaks are listed in Table 12.

TABLE 11 XRPD peaks observed for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Form D. 2θ (°) d space (Å) Intensity (%)  6.0 ± 0.214.688 ± 0.488  66  6.3 ± 0.2 13.925 ± 0.439  81 10.7 ± 0.2 8.247 ±0.153 50 12.0 ± 0.2 7.358 ± 0.122 42 12.7 ± 0.2 6.981 ± 0.110 36 15.6 ±0.2 5.680 ± 0.072 13 16.2 ± 0.2 5.479 ± 0.067 12 16.3 ± 0.2 5.421 ±0.066 29 16.7 ± 0.2 5.303 ± 0.063 11 17.9 ± 0.2 4.954 ± 0.055 32 18.1 ±0.2 4.908 ± 0.054 100 19.1 ± 0.2 4.656 ± 0.048 9 19.8 ± 0.2 4.480 ±0.045 4 19.9 ± 0.2 4.455 ± 0.044 4 20.3 ± 0.2 4.382 ± 0.043 3 20.3 ± 0.24.363 ± 0.042 4 21.4 ± 0.2 4.153 ± 0.038 17 21.7 ± 0.2 4.090 ± 0.037 6022.2 ± 0.2 4.006 ± 0.036 19 22.4 ± 0.2 3.968 ± 0.035 8 22.8 ± 0.2 3.898± 0.034 4 23.7 ± 0.2 3.744 ± 0.031 9 24.2 ± 0.2 3.683 ± 0.030 12 24.9 ±0.2 3.572 ± 0.028 18 25.5 ± 0.2 3.491 ± 0.027 9 25.7 ± 0.2 3.468 ± 0.02713 26.9 ± 0.2 3.309 ± 0.024 6 27.2 ± 0.2 3.276 ± 0.024 23 27.3 ± 0.23.268 ± 0.024 17 27.4 ± 0.2 3.258 ± 0.023 29 27.6 ± 0.2 3.230 ± 0.023 627.9 ± 0.2 3.193 ± 0.022 9 28.1 ± 0.2 3.168 ± 0.022 18 28.2 ± 0.2 3.159± 0.022 14 28.4 ± 0.2 3.137 ± 0.022 7 28.6 ± 0.2 3.121 ± 0.021 11 29.1 ±0.2 3.065 ± 0.021 7 29.2 ± 0.2 3.055 ± 0.020 6 29.4 ± 0.2 3.031 ± 0.0204 29.7 ± 0.2 3.005 ± 0.020 6 30.1 ± 0.2 2.967 ± 0.019 6

TABLE 12 Prominent XRPD peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Form D. 2θ (°) d space (Å) Intensity (%)  6.0 ± 0.214.688 ± 0.488  66  6.3 ± 0.2 13.925 ± 0.439  81 10.7 ± 0.2 8.247 ±0.153 50 12.0 ± 0.2 7.358 ± 0.122 42 12.7 ± 0.2 6.981 ± 0.110 36 15.6 ±0.2 5.680 ± 0.072 13 16.2 ± 0.2 5.479 ± 0.067 12 16.3 ± 0.2 5.421 ±0.066 29 16.7 ± 0.2 5.303 ± 0.063 11 17.9 ± 0.2 4.954 ± 0.055 32 18.1 ±0.2 4.908 ± 0.054 100 21.4 ± 0.2 4.153 ± 0.038 17 21.7 ± 0.2 4.090 ±0.037 60 22.2 ± 0.2 4.006 ± 0.036 19 24.2 ± 0.2 3.683 ± 0.030 12 24.9 ±0.2 3.572 ± 0.028 18 25.7 ± 0.2 3.468 ± 0.027 13 27.2 ± 0.2 3.276 ±0.024 23 27.3 ± 0.2 3.268 ± 0.024 17 27.4 ± 0.2 3.258 ± 0.023 29 28.1 ±0.2 3.168 ± 0.022 18 28.2 ± 0.2 3.159 ± 0.022 14 28.6 ± 0.2 3.121 ±0.021 11

FT-IR was performed on a sample of Form D as described in Example 1(FIG. 11). Observed peaks from FIG. 11 are listed in Table 13.

TABLE 13 Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Form D. Position (cm⁻¹) Intensity 687 0.0579 6900.057 698 0.0283 712 0.0567 728 0.0183 740 0.0162 745 0.0172 750 0.0147763 0.0177 787 0.0527 791 0.0353 834 0.0372 846 0.0406 852 0.0298 8680.0215 876 0.0185 891 0.0161 920 0.0113 946 0.0294 979 0.0085 10010.0083 1041 0.0223 1067 0.0216 1094 0.0206 1123 0.017 1163 0.0402 11940.0146 1215 0.0341 1239 0.0478 1284 0.0248 1309 0.0269 1329 0.0212 13460.0207 1382 0.0162 1394 0.0159 1451 0.0276 1471 0.0291 1500 0.0373 15370.0375 1574 0.045 1599 0.0292 1613 0.0585 1631 0.0652 1647 0.0542 18230.0044 2736 0.0129 2939 0.0107 2973 0.0115 3124 0.0113 3163 0.0111 32480.0109

DSC was performed on a sample of Form D as described in Example 1 (FIG.12) and showed endotherms having peak maxima at temperatures ofapproximately 156 and 204° C., respectively. The DSC is consistent withthat of Form A, except that the first two endotherms related to themelting and loss of water are not present in the DSC trace of Form D.Thus, the DSC is consistent with the conclusion that Form D isdehydrated Form A.

Example 6 Comparison of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic Acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Forms A and C by RamanSpectroscopy

Samples of each of4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide Forms A and C were prepared at60 mg/ml in a ethanol:methanol:isopropanol (90:5:5) mixture at 24° C.Raman spectroscopy was performed on each sample and on the solvent aloneas described in Example 1.

Results for a scan of wavelengths 1000-1600 cm⁻¹ are shown in FIG. 13. Aclear characteristic peak at about 1165 cm⁻¹ was observed for Form A.

Results for a scan of wavelengths 950-1030 cm⁻¹ are shown in FIG. 14. Acharacteristic peak at about 983 cm⁻¹ was observed for Form A and acharacteristic peak at about 987 cm⁻¹ was observed for Form C.

Although illustrative embodiments of the present invention have beendescribed herein, it should be understood that the invention is notlimited to those described, and that various other changes ormodifications may be made by one skilled in the art without departingfrom the scope or spirit of the invention.

CITED REFERENCES

-   1. Kohno M, Pouyssegur J (2006) Targeting the ERK signaling pathway    in cancer therapy. Ann Med 38: 200-211.-   2. Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., New York.-   3. Lee D C, Webb M L (2003) Pharmaceutical Analysis. John Wiley &    Sons, Inc., New York: 255-257.-   4. Peterson M L, Hickey M B, Zaworotko M J and Almarsson O (2006)    Expanding the Scope of Crystal Form Evaluation in Pharmaceutical    Science. J Pharm Pharmaceut Sci 9(3):317-326.-   5. Pierce Catalog and Handbook, 1994-1995; Pierce Chemical Co.,    Rockford, Ill.-   6. Remington, The Science and Practice of Pharmacy (21st Edition,    Lippincott Williams and Wilkins, Philadelphia, Pa.-   7. The United States Pharmacopeia-National Formulary, The United    States Pharmacopeial Convention, Rockville, Md.    All documents cited in this application are hereby incorporated by    reference as if recited in full herein.

What is claimed is:
 1. A method for treating a cancer in a subject inneed thereof, comprising administering to the subject a combinationof: 1) an effective amount of a first agent selected from: i)crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide, or ii)crystalline free base4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide, or iii) crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl, or iv) crystalline4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl hydrate, or v) acrystalline compound of formula (I):

 having an X-ray powder diffraction (XRPD) pattern comprisingcharacteristic peaks at about 9.1 15.4, 19.5 and 21.4° 2θ, or vi) acrystalline hydrochloride salt of a compound of formula (I):

 having an X-ray powder diffraction (XRPD) pattern comprisingcharacteristic peaks at about 6.7 11.0, 17.6 and 19.9° 2θ, or vii) apharmaceutical composition comprising at least one of i to vi, and 2) aneffective amount of a second agent selected from the group consisting ofan anaplastic lymphoma kinase (ALK) inhibitor, a B-Raf inhibitor, anepidermal growth factor (EGFR) inhibitor, an ERK inhibitor, a Januskinase inhibitor, an MEK inhibitor, a mammalian target of rapamycin(mTOR) inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, a RASinhibitor, and combinations thereof.
 2. The method of claim 1, whereinthe second agent is an ALK inhibitor selected from the group consistingof crizotinib (Pfizer, New York, N.Y.), CH5424802 (Chugai PharmaceuticalCo., Tokyo, Japan), GSK1838705 (GlaxoSmithKline, United Kingdom), Chugai13d (Chugai Pharmaceutical Co., Tokyo, Japan), CEP28122 (TevaPharmaceutical Industries, Ltd., Israel), AP26113 (AriadPharmaceuticals, Cambridge, Mass.), Cephalon 30 (Teva PharmaceuticalIndustries, Ltd., Israel), X-396 (Xcovery, Inc., West Palm Beach, Fla.),Amgen 36 (Amgen Pharmaceuticals, Thousand Oaks, Calif.), ASP3026(Astellas Pharma US, Inc., Northbrook, Ill.), Amgen 49 (AmgenPharmaceuticals, Thousand Oaks, Calif.), pharmaceutically acceptablesalts thereof, and combinations thereof.
 3. The method of claim 1,wherein the second agent is an EGFR inhibitor selected from the groupconsisting of (+)-Aeroplysinin-1 (CAS #28656-91-9),3-(4-Isopropylbenzylidenyl)-indolin-2-one, ABT-806 (Life SciencePharmaceuticals), AC-480 (Bristol-Myers Squibb), afatinib (BoehringerIngelheim), AG 1478 (CAS #153436-53-4), AG 494 (CAS #133550-35-3), AG555 (CAS #133550-34-2), AG 556 (CAS #133550-41-1), AG 825 (CAS#149092-50-2), AG-490 (CAS #134036-52-5), antroquinonol (GoldenBiotechnology), AP-26113 (Ariad), ARRY334543 (CAS #845272-21-1), AST1306 (CAS #897383-62-9), AVL-301 (Celgene), AZD8931 (CAS #848942-61-0),BIBU 1361 (CAS #793726-84-8), BIBX 1382 (CAS #196612-93-8), BMS-690514(Bristol-Myers Squibb), BPIQ-I (CAS #174709-30-9), Canertinib (Pfizer),cetuximab (Actavis), cipatinib (Jiangsu Hengrui Medicine), CL-387,785(Santa Cruz Biotech), compound 56 (CAS #171745-13-4), CTX-023 (CytomXTherapeutics), CUDC101 (Curis), dacomitinib (Pfizer), DAPH (CAS#145915-58-8), daphnetin (Santa Cruz Biotech), dovitinib lactate(Novartis), EGFR Inhibitor (CAS #879127-07-8), epitinib (Hutchison ChinaMediTech), erbstatin Analog (CAS #63177-57-1), erlotinib (Astellas),gefitinib (AstraZeneca), GT-MAB 5.2-GEX (Glycotope), GW 583340 (CAS#388082-81-3), GW2974 (CAS #202272-68-2), HDS 029 (CAS #881001-19-0),Hypericin (Santa Cruz Biotech), icotinib hydrochloride (Betapharma),JNJ-26483327 (Johnson & Johnson), JNJ-28871063 (Johnson & Johnson),KD-020 (Kadmon Pharmaceuticals), lapatinib ditosylate (GlaxoSmithKline),Lavendustin A (Sigma), Lavendustin C (Sigma), LY-3016859 (Eli Lilly),MEHD-7945A (Hoffmann-La Roche), MM-151 (Merrimack), MT-062 (MedisynTechnologies), necitumumab (Eli Lilly), neratinib (Pfizer), nimotuzumab(Center of Molecular Immunology), NT-004 (New-Gen Therapeutics),pantiumumab (Amgen), PD 153035 (CAS #153436-54-5), PD 161570 (CAS#192705-80-9), PD 168393, PD 174265 (CAS #216163-53-0), pirotinib(Sihuan Pharmaceutical), poziotinib (Hanmi), PP 3 (CAS #5334-30-5),PR-610 (Proacta), pyrotinib (Jiangsu Hengrui Medicine), RG-13022 (CAS#136831-48-6), rindopepimut (Celldex Therapeutics), RPI-1 (CAS#269730-03-2), S-222611 (Shionogi), TAK 285 (CAS #871026-44-7), TAS-2913(Taiho), theliatinib (Hutchison China MediTech), Tyrphostin 47(RG-50864, AG-213) (CAS #118409-60-2), Tyrphostin 51 (CAS #122520-90-5),Tyrphostin AG 1478 (CAS #175178-82-2), Tyrphostin AG 183 (CAS#126433-07-6), Tyrphostin AG 528 (CAS #133550-49-9), Tyrphostin AG 99(CAS #118409-59-9), Tyrphostin B42 (Santa Cruz Biotech), Tyrphostin B44(Santa Cruz Biotech), Tyrphostin RG 14620 (CAS #136831-49-7), vandetanib(AstraZeneca), varlitinib (Array BioPharma), vatalanib (Novartis), WZ3146 (CAS #1214265-56-1), WZ 4002 (CAS #1213269-23-8), WZ8040 (CAS#1214265-57-2), XL-647 (Exelixis), Z-650 (HEC Pharm), ZM 323881 (CAS#324077-30-7), pharmaceutically acceptable salts thereof, andcombinations thereof.
 4. The method of claim 3, wherein the EGFRinhibitor is selected from the group consisting of panitumumab,erlotinib, pharmaceutically acceptable salts thereof, and combinationsthereof.
 5. The method of claim 1, wherein the second agent is an ERKinhibitor selected from the group consisting of AEZS-131 (AetemaZentaris), AEZS-136 (Aeterna Zentaris), SCH-722984 (Merck & Co.),SCH772984 (Merck & Co.), SCH-900353 (MK-8353) (Merck & Co.),pharmaceutically acceptable salts thereof, and combinations thereof. 6.The method of claim 1, wherein the second agent is a Janus kinaseinhibitor selected from the group consisting of ruxolitinib (IncyteCorporation, Wilmington, Del.), baricitinib (Incyte Corporation,Wilmington, Del.), tofacitinib (Pfizer, New York, N.Y.), VX-509 (VertexPharmaceuticals, Inc., Boston, Mass.), GLPG0634 (Galapagos NV, Belgium),CEP-33779 (Teva Pharmaceuticals, Israel), pharmaceutically acceptablesalts thereof, and combinations thereof.
 7. The method of claim 1,wherein the second agent is an mTOR inhibitor selected from the groupconsisting of zotarolimus (AbbVie), umirolimus (Biosensors),temsirolimus (Pfizer), sirolimus (Pfizer), sirolimus NanoCrystal (ElanPharmaceutical Technologies), sirolimus TransDerm (TransDerm),sirolimus-PNP (Samyang), everolimus (Novartis), biolimus A9(Biosensors), ridaforolimus (Ariad), rapamycin, TCD-10023 (Terumo),DE-109 (MacuSight), MS-R001 (MacuSight), MS-R002 (MacuSight), MS-R003(MacuSight), Perceiva (MacuSight), XL-765 (Exelixis), quinacrine(Cleveland BioLabs), PKI-587 (Pfizer), PF-04691502 (Pfizer), GDC0980(Genentech and Piramed), dactolisib (Novartis), CC-223 (Celgene),PVVT-33597 (Pathway Therapeutics), P-7170 (Piramal Life Sciences),LY-3023414 (Eli Lilly), INK-128 (Takeda), GDC-0084 (Genentech), DS-7423(Daiichi Sankyo), DS-3078 (Daiichi Sankyo), CC-115 (Celgene), CBLC-137(Cleveland BioLabs), AZD-2014 (Astra-Zeneca), X-480 (Xcovery), X-414(Xcovery), EC-0371 (Endocyte), VS-5584 (Verastem), PQR-401 (Piqur),PQR316 (Piqur), PQR-311 (Piqur), PQR-309 (Piqur), PF-06465603 (Pfizer),NV-128 (Novogen), nPT-MTOR (Biotica Technology), BC-210 (BioticaTechnology), WAY-600 (Biotica Technology), WYE-354 (Biotica Technology),WYE-687 (Biotica Technology), LOR-220 (Lorus Therapeutics), HMPL-518(Hutchison China MediTech), GNE317 (Genentech), EC-0565 (Endocyte),CC-214 (Celgene), ABTL-0812 (Ability Pharmaceuticals), pharmaceuticallyacceptable salts thereof, and combinations thereof.
 8. The method ofclaim 1, wherein the second agent is a RAS inhibitor selected from thegroup consisting of tipifarnib, lonafarnib, salirasib and TLN-4601),DCAI, Kobe0065, Kobe2602, HBS 3, AIK-4 (Allinky), pharmaceuticallyacceptable salts thereof, and combinations thereof.
 9. The method ofclaim 1, wherein the first and the second agents are administered to thesubject simultaneously.
 10. The method of claim 1, wherein the first andthe second agents are administered to the subject sequentially.